Aminoalkoxyphenyl derivatives, process of preparation and compositions containing the same

ABSTRACT

The present invention relates to aminoalkoxyphenyl compounds of formula: ##STR1## in which: B is selected from --S--, --SO-- and --SO 2  --, 
     R 1  and R 2 , which are identical or different, are selected from hydrogen, methyl, ethyl and halogen, 
     A is selected from a straight- or branched-alkylene radical having from 2 to 5 carbon atoms, a 2-hydroxypropylene radical, and a 2-(lower alkoxy) propylene radical, 
     R 3  is selected from C 1  -C 8  alkyl and a radical of formula: 
     
         --Alk--Ar 
    
      in which Alk is selected from a single bond and a linear- or branched-alkylene radical having from 1 to 5 carbon atoms; and Ar is selected from pyridyl, phenyl, 2-3-methyleneoxyphenyl, 3,4-methylenedioxyphenyl and phenyl substituted with one or more substituents, which may be identical or different, selected from halogen atoms, C 1  -C 8  alkyl groups and C 1  -C 8  alkoxy groups, 
     R 4  is selected from hydrogen and C 1  -C 8  alkyl, or 
     R 3  and R 4 , when taken together, denote a 1,4-tetra-methylene, 1,5-pentamethylene, 3-oxa-1,5-pentamethylene, 3-aza-1,5-pentamethylene, 3-methylaza-1,5-pentamethylene, 3-phenylaza-1,5-pentamethylene or --CH═CH--N═CH-- radical, 
     R is selected from hydrogen, C 1  -C 8  alkyl, C 3  -C 6 , cycloalkyl, benzyl, phenyl optionally substituted with one or more substituents, which may be identical or different, selected from halogen, C 1  -C 4  alkyl and C 1  -C 4  alkoxy as well as a pharmaceutically acceptable salt thereof.

This application is a divisional of application Ser. No. 07/596,334,filed Oct. 12, 1990, which is a divisional of application Ser. No.07/306,499, filed Feb. 6, 1989, now U.S. Pat. No. 4,994,474, which is acontinuation-in-part of application Ser. No. 07/082,554, filed Aug. 7,1987, now U.S. Pat. No. 4,957,925, which is a continuation-in-part ofapplication Ser. No. 07/006,233, filed Jan. 23, 1987, now abandoned.

The present invention relates to a new carbocyclic or heterocyclicderivatives and to a process for preparing them.

More particularly, the invention relates to the novel aminoalkoxyphenylderivatives represented by the general formula: ##STR2## in which: Brepresents a --S--, --SO-- or --SO₂ -- group,

R₁ and R₂, which are identical or different, each denote hydrogen, amethyl or ethyl radical or a halogen such as chlorine, bromine oriodine,

A denotes a straight- or branched-alkylene radical having from 2 to 5carbon atoms or a 2-hydroxypropylene radical in which the hydroxy isoptionally substituted by a lower alkyl radical,

R₃ denotes an alkyl radical or a radical of formula

    --Alk--Ar

in which Alk denotes a single bond or a linear- or branched-alkyleneradical having from 1 to 5 carbon atoms and Ar denotes a pyridyl,phenyl, 2,3-methylenedioxyphenyl or 3,4-methylenedioxyphenyl radical ora phenyl group substituted with one or more substituents, which may beidentical or different, selected from halogen atoms, lower alkyl groupsor lower alkoxy groups,

R₄ denotes hydrogen or an alkyl radical, or R₃ and R₄ when takentogether, denote an alkylene or alkenylene radical having from 3 to 6carbon atoms and optionally substituted with a phenyl radical oroptionally interrupted by --O--, --N═ or >N--R₁₁, R₁₁ denoting hydrogenor a lower alkyl, phenyl, diphenylmethyl, benzyl or halogenobenzylradical,

Cy represents a group of formula: ##STR3## R represents hydrogen, analkyl radical, a cycloalkyl radical, a benzyl radical or a phenylradical optionally substituted with one or more substituents, which maybe identical or different, selected from halogen atoms, for examplefluorine, chlorine, bromine atoms and from lower alkyl, lower alkoxy ornitro groups,

R₅ and R₆ are taken together with the carbon atom to which they areattached to form:

an optionally aromatic mono- or di-cyclic carbocyclic group having from5 to 10 carbon atoms and optionally substituted by a R group in theα-position with respect to the methyne group,

an optionally aromatic 5-membered heterocyclic group, the heteroatoms orheterogroups being selected from the groups O, S, N, >N--R₁₁ ; O and N;O and >N--R₁₁ ; S and N; S and >N--R₁₁ ; N and N; N and >N--R₁₁, theheterocyclic group being optionally substituted by a R group in theα-position with respect to the methyne group and optionally substitutedby one or two groups selected from lower alkyl and phenyl groups,

an optionally aromatic 6- to 10-membered mono- or di-cyclic heterocyclicgroup, the heteroatoms or heterogroups being selected from the groups O,S, N,>N--R₁₁ ; O and N; O and >N--R₁₁ ; S and N; S and >N--R₁₁ ; N andN; N and >N--R₁₁ ; the heterocyclic group being optionally substitutedby a R group in the α-position with respect to the methyne group,

R₇ and R₈, which are the same or different, each represent hydrogen, alower alkyl radical or a phenyl radical or when they are taken togetherwith the carbon atoms to which they are attached represent an optionallyaromatic 6-membered carbocyclic ring,

R₉ represents oxygen or sulphur

R₁₀ represents oxygen, sulphur or a group>N--R₁₁

R₁₂ and R₁₃, which are identical or different, each represent hydrogen,a lower alkyl radical or a benzoyl radical

with the proviso that when Cy represents a benzo[b] furyl or benzo[b]thienyl group and B represents a --SO₂ -- group, R₃ represents a radical--Alk--Ar and with the proviso that Cy does not represent a1-indolizinyl radical.

In the present context, both in the description and in the claims, thefollowing meaning attaches to the terms stated above:

"alkyl" denotes straight- or branched-saturated aliphatic hydrocarbonresidues having up to 8 carbon atoms, such as methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, neopentyl, n-hexyl,n-heptyl or n-octyl,

"lower alkyl" denotes saturated aliphatic hydrocarbon residues having upto 4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl,iso-butyl, tert-butyl, 1-methylpropyl,

"lower alkoxy" denotes a hydroxy group substituted with a lower alkylgroup as defined above,

"cycloalkyl" denotes an alicyclic ring having from 3 to 6 carbon atoms.

Thus, taking into account the meanings given above:

R can denote, in particular, a methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, tert-butyl, 1-methylpropyl, n-pentyl, neopentyl,phenyl, monofluoro, monochloro- or monobromophenyl, difluoro-, dichloro-or dibromophenyl, monomethyl- or dimethylphenyl, or monomethoxy- ordimethoxyphenyl radical, a methylphenyl radical substituted with ahalogen atom or a cyclopropyl radical,

A can denote, in particular, a 1,2-ethylene, 1,3-propylene,2-methyl-1,3-propylene, 1,4-tetramethylene or 1,5-pentamethylene chain,

R₃ can denote, in particular, a methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, tert-butyl, 1-methyl-propyl, n-pentyl, n-hexyl,n-heptyl, n-octyl, phenyl, benzyl or phenethyl radical, a methoxyphenylor a dimethoxyphenethyl, for example 3,4-dimethoxyphenethyl radical, adimethylphenethyl, dimethoxyphenyl, dimethoxybenzyl or pyridylethylradical or a phenethyl radical substituted in the aromatic portion, withmethyl and methoxy radicals,

R₄ can denote, in particular, a methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, tert-butyl, n-pentyl, neopentyl, n-hexyl, n-heptyl orn-octyl radical,

R₃ and R₄, taken together, can denote, in particular, a1,4-tetramethylene, 1,5-pentamethylene, 3-oxo-1,5-pentamethylene,3-aza-1,5-pentamethylene, 3-methyl-aza-1,5-pentamethylene,3-phenylaza-1,5-pentamethylene or --CH═CH--N═CH-- radical, so that R₃and R₄, taken with the nitrogen atom to which they are attached, candenote, in particular, pyrrolidinyl, piperidyl, morpholinyl,piperazinyl, 4-methylpiperazinyl, 4-phenylpiperazinyl or 1H-imidazolylradical.

Cy can denote, in particular, a phenyl, cyclohexenyl, indenyl, naphthyl,dihydronaphthyl, pyridyl, dihydropyridyl, furyl, dihydrofuryl, thienyl,dihydrothienyl, pyrrolyl, dihydropyrrolyl, pyrazolyl, imidazolyl,pyrimidyl, pyrazinyl, pyridazinyl, oxazolyl, isoxaolyl, thiazolyl,benzofuryl, benzothienyl, indolyl, benzimidazolyl, benzoxazolyl,quinolinyl, benzisoxazolyl, cinnolinyl, quinoxalinyl, quinazolinyl,indolizin-3-yl, thienopyridyl, tetrahydrothienopyridyl, pyrrolopyridyl,pyrazolopyridyl, pyrrolopyridazinyl, imidazopyridyl, dihydrofuranonyl,imidazolinonyl, chromonyl radical.

A particular valuable class of compounds of formula (1) are those inwhich Cy represents an indolizin-3-yl group.

Another class of compounds are those in which R₁ and R₂ each arehydrogen.

Another class of compounds of formula (1) are those in which R₃represents a group of formula --Alk--Ar.

A particular class of useful compounds of formula (1) are those in whichR₃ represents hydrogen and R₄ represents tert-butyl or R₃ and R₄ eachrepresent n-propyl or n-butyl.

Particularly useful compounds of formula (1) are those in which thechain ##STR4## represents a[N-methyl-N-(3,4-dimethoxy-β-phenethyl)amino]propyloxy group.

Other valuable compounds of formula (1) are those in which R representsan isopropyl or cyclopropyl group.

The invention also relates to the pharmaceutically acceptable salts ofthe compounds of formula (1) formed with an organic or inorganic acid.

As examples of organic salts of this type, there may be mentioned theoxalate, maleate, fumarate, methanesulphonate, benzoate, ascorbate,pamoate, succinate, hexamate, bismethylenesalicylate,ethanedisulphonate, acetate, propionate, tartrate, salicylate, citrate,gluconate, lactate, malate, cinnomate, madelate, citraconate, aspartate,palmitate, stearate, itaconate, glycolate, p-aminobenzoate, glutamate,benzenesulphonate and theopylline-acetate, as well as the salts formedwith an amino acid such as the lysine or histidine salt.

As examples of inorganic salts of this type, the hydrochloride,hydrobromide, sulphate, sulphamate, phosphate and nitrate may bementioned.

Another object of the invention relates to the N-oxide derivatives ofthe compounds of formula (1).

The compounds of formula (1) can exist, in some cases, in the form ofoptical isomers, in particular as a result of the asymmetric carbonpresent when A represents a 2-hydroxypropylene chain.

The invention relates, at the same time, to all the isomers of thecompounds of formula (1), the isomers being considered in thedextrorotatory or laevorotatory form, or in the form of a mixture, forexample in the form of a racemic mixture.

It has been found that the aminoalkoxyphenyl derivatives of theinvention possess exceptional pharmacological properties, especiallycalcium transport inhibitory properties, as well as bradycardic,hypotensive and antiadrenergic properties.

From this viewpoint, the preferred compounds of the invention are thosein which B represents a --SO₂ -- group.

These properties are capable of making the compounds in question veryuseful in the treatment of certain pathological syndromes of thecardiovascular system, especially in the treatment of angina pectoris,hypertension, arrhythmia and cerebral circulatory insufficiency.

In the antitumour field, the compounds of the invention may be useful aspotentiators of anticancer drugs.

Consequently, the invention also relates to pharmaceutical or veterinarycompositions containing, as active principle, at least oneaminoalkoxyphenyl derivative of formula (1) or a pharmaceuticallyacceptable salt of this derivative, or an N-oxide derivative thereof, incombination with a pharmaceutical vehicle or a suitable excipient.

Another object of the invention relates to a method for treatingpathological syndromes of the cardiovascular system especially anginapectoris, hypertension, arrhythmia and cerebral vascular insufficiencyin a host in need of such treatment comprising the administration tothis host of an effective dose of an aminoalkoxyphenyl derivative of theinvention.

Depending on the administration route selected, the daily dosage for ahuman being weighing 60 kg will be between 2 and 500 mg of activeprinciple.

The compounds of formula (1) can be obtained:

I. When B represents a --S-- or --SO₂ -- group and A represents analkylene radical, by condensing, in the presence of an acid acceptor andin a polar solvent such as dimethylsulphoxide or an alcohol, for examplebutanol, or a ketone such as methyl ethyl ketone, or a non-polar solventsuch as an aromatic hydrocarbon, for example benzene, toluene or xylene,a 4-alkoxyphenyl derivative of general formula: ##STR5## in which B'represents a --S-- or --SO₂ -- group, Cy, R₁ and R₂ have the samemeaning as above, A represents an alkylene radical as defined in theformula (1) and X represents a halogen atom, preferably bromine, or analkylsulphonyloxy group having from 1 to 4 carbon atoms such as forexample, methanesulphonyloxy, or an arylsulphonyloxy group having from 6to 10 carbon atoms, such as benzenesulphonyloxy orp-toluenesulphonyloxy, with an amine of general formula: ##STR6## inwhich R₃ and R₄ have the same meaning as above to form the desiredaminoalkoxyphenyl derivative of formula (1) in the form of a free base.

In general, the condensation in question is performed at a temperaturebetween room-temperature and the refluxing-temperature of the medium,the acid acceptor being, for example, an alkali metal carbonate orhydroxide or an excess of amine of formula (3).

The compounds of formula (2) in question can be obtained:

a) when X is a halogen, by condensation of a 4-hydroxyphenyl derivativeof general formula: ##STR7## in which Cy, B', R₁ and R₂ have the samemeaning as above, with a dihaloalkane of general formula

    Hal--A--Hal                                                (5)

in which A denotes an alkylene radical as defined in the formula (1) andHal denotes a halogen atom, preferably bromine, this reaction beingperformed under reflux in a solvent such as methyl ethyl ketone orN,N-dimethylformamide and in the presence of a basic agent such as analkali metal carbonate, for example potassium carbonate, an alkali metalhydride such as sodium hydride, an alkali metal hydroxide, for examplesodium or potassium hydroxide, or an alkali metal alcoholate, forexample sodium methylate or ethylate,

b) when X denotes an alkylsulphonyloxy or arylsulphonyloxy group, bycondensation of a halide of general formula:

    Hal--W

in which Hal has the same meaning as above and W denotes analkylsulphonyl radical having from 1 to 4 carbon atoms, for examplemethanesulphonyl, or an arylsulphonyl radical having from 6 to 10 carbonatoms, for example benzenesulphonyl or p-toluenesulphonyl, in a solventwhich is an acid acceptor, for example pyridine, with a 4-hydroxyalkoxyderivative of general formula: ##STR8## in which Cy, B', R₁ and R₂ havethe same meaning as above and A denotes an alkylene radical as definedin formula (1).

As regards the compounds of formula (6), these can be prepared bycondensing, in a suitable solvent such as N,N-dimethylformamide and inthe presence of a basic agent such as an alkali metal carbonate, forexample potassium carbonate, an alkali metal hydroxide such as sodium orpotassium hydroxide, an alkali metal hydride such as sodium hydride oran alkali metal alcoholate, for example sodium methylate or ethylate, a4-hydroxyphenyl, derivative of formula (4) above with a halogenatedalcohol of general formula:

    Hal--A--OH                                                 (7)

in which A denotes an alkylene radical as defined in the formula (1) andHal has the same meaning as above.

Compounds of formula (4) are known products, for instance thosecompounds in which Cy represents a benzofuryl or benzothienyl group andB' represents a --SO₂ -- group. These compounds are disclosed in U.S.Pat. No. 4,117,128.

The other compounds of formula (4) can be prepared in a generalprocedure, by adapting to the desired compound the method described inthe aforesaid U.S. patent or the methods described hereunder.

In most cases, those compounds of formula (4) can be obtained by fixinga 4-0-protected benzenesulphonyl or phenylthio chain to the requiredcarbocycle or heterocycle using a Friedel-Crafts reaction anddeprotecting the oxygen in the 4-position of the benzenesulphonyl orphenylthio group by means of classical procedures to regenerate the OHgroup.

Hereunder are examples of methods commonly used for preparingderivatives of formula (4):

a) Compounds of formula (4) in which Cy represents a group (D)

1) The compounds of formula (4) in which Cy represents a2-R-indolizon-3-yl group can be prepared by reacting an indolizinederivative of general formula: ##STR9## in which R has the same meaningas above and R₁₄ represents a lower alkyl radical preferably ethyl, witha halide of general formula: ##STR10## in which B', R₁, R₂ and Hal havethe same meaning as above and in the presence of a Friedel-Craftscatalyst such as aluminum chloride to provide a compound of generalformula: ##STR11## in which B', R, R₁, R₂ and R₁₄ have the same meaningas above.

The compound of formula (10) is subsequently demethylated using anethanethiol/aluminum chloride mixture to give a 4-methoxyphenylderivative of general formula: ##STR12## in which B', R, R₁ and R₂ havethe same meaning as above which, when heated to about 200° C. providesthe required compound of formula (4).

The compounds of formula (8) are either known compounds having beenpublished in J. Chem Soc. 1962 pp. 2627-2629 or compounds which can beprepared in accordance with the method described therein.

2) The compounds of formula (4) in which Cy represents a2-R-imidazo[1,2-a]pyrid-3-yl group can be prepared from a2-R-imidazo[1,2-a]pyridine with a halide of formula (9) and in thepresence of a Friedel-Crafts catalyst such as aluminum chloride toprovide a compound of general formula: ##STR13## in which B', R, R₁ andR₂ have the same meaning as above.

The compound of formula (12) is subsequently demethylated using anappropriate agent for instance hydrobromic acid or anethanethiol/aluminum chloride mixture to give the required compound offormula (4).

2-Aryl-imidazo[1,2-a]pyridines are known from J. Med. Chem. 8, p. 305(1965). The other 2-R-imidazo[1,2-a]pyridines can be obtained inaccordance with the method described in the aforesaid reference or usingclassical procedures.

Alternatively, the compounds of formula (12) can be obtained from a2-R-3-halo-imidazo[1,2-a]pyridine and the alkali metal salt of a4-methoxy derivative of formula (15).

3) The compounds of formula (4) in which Cy represents a pyridyl or3-R-4-pyridyl group can be obtained by demethylating with an appropriateagent such as aqueous hydrobromic acid, a 4-methoxyphenyl derivative ofgeneral formula: ##STR14## in which B', R₁ and R₂ have the same meaningas above and R has the same meaning as above with the exception ofhydrogen, to provide the required compounds of formula (4).

The compounds of formulae (13) and (13') in which B' represents a --SO₂-- group can be prepared by oxidizing a sulfide derivative of generalformula: ##STR15## in which R₁ and R₂ have the same meaning as above andR has the same meaning as in formula (13) or (13').

Compounds of formula (14) are known having been described in U.S. Pat.No. 4,128,552. The other compounds of formula (14) can be obtained inaccordance with the method described in the aforesaid U.S. Patent whilethose compounds of formula (14') can be prepared from a 3-R-pyridine, inwhich R is other than hydrogen, by oxidation with hydrogen peroxide inacetic acid to provide the corresponding 3-R-pyridine-N-oxide which whenreacted with a nitric acid/sulphuric acid mixture gives rise to thecorresponding 3-R-4-nitro-pyridine-N-oxide.

This nitro derivative is then reacted first with acetyl bromide, thenwith iron powder in acetic acid to give the corresponding3-R-4-bromo-pyridine which, when treated with a thiophenol derivative ofgeneral formula: ##STR16## in which R₁ and R₂ have the same meaning asabove and M represents an alkali metal atom such as sodium, provides therequired compound of formula (14').

4) The compounds of formula (4) in which Cy represents a2-R-quinolin-3-yl group can be prepared by reacting an α-haloketone ofgeneral formula: ##STR17## in which R and Hal have the same meaning asabove, with a metal derivative of general formula: ##STR18## in which M,B', R₁ and R₂ have the same meaning as above and Ts represents ap-toluenesulphonyl group, to provide a ketone of general formula:##STR19## in which B', R, R₁ R₂ and Ts have the same meaning as above.

This ketone of formula (18) when treated with 2-amino-benzaldehyde[Helv. Chem Act. vol. XVIII, p. 1235 (1935)] gives the 4-methoxyphenylderivative of general formula: ##STR20## in which B', R, R₁, R₂ and Tshave the same meaning as above, which is subsequently hydrolysed inbasic medium for instance in aqueous alkali metal hydroxide, to providethe required compound of formula (4).

5) The compounds of formula (4) in which Cy represents a3-R-cinnolin-4-yl or 4-R-cinnolin-3-yl group can be obtained by reactinga 3-R-4-halogenocinnoline (J. Chem Soc. 1953, p. 609) with a thiophenolderivative of general formula: ##STR21## in which M, R₁, R₂ and Ts havethe same meaning as above and B' represents a --S-- group to provide the4-tosyloxyphenyl derivative of general formula: ##STR22## in which R,R₁, R₂ and Ts have the same meaning as above and B' represents a --S--group.

The 4-tosyloxyphenyl derivative of formula (21) or (21') is subsequentlyhydrolysed in basic medium for instance in aqueous alkali metalhydroxide to give the required compound of formula (4) in which B'represents a --S-- group. Compounds of formula (20) in which --OTs isreplaced by --OCH₃ can also be used. In such case the correspondingcompound of formula (21) or (21') is demethylated using for instancehydrobromic acid.

The sulphide derivative of formula (21) or (21') when oxidized with asuitable agent such as hydrogen peroxide in acetic acid or potassiumpermanganate, provides the compound of formula (21) or (21') in which B'represents a --SO₂ -- group, which compound after hydrogenation on acatalyst such as palladium charcoal or platinum charcoal gives therequired compounds of formula (4) in which B' represents a --SO₂ --group.

Alternatively the compounds of formula (4) in question in which B'represents a --SO₂ -- group can be obtained from a3-R-4-halogenocinnoline or a 4-R-3-halogenocinnoline by reacting with abenzenesulphonyl derivative of general formula (20) in which B'represents a --SO₂ -- group to obtain a compound of formula (21) or(21') in which B' represents a --SO₂ -- group which is detosylated asdescribed above to provide the required compound of formula (4).

6) The compounds of formula (4) in which Cy represents a6-R-pyrrolo[1,2-b]pyridazin-5-yl group can be prepared by reacting a3-halogenomethylpyridazine with a metal derivative of formula (17) toprovide a pyridazine derivative of general formula: ##STR23## in whichB', R₁, R₂ and Ts have the same meaning as above, which is subsequentlyreacted with an α-haloketone of formula (16) in the presence of anon-nucleophilic base such as for example1,8-diazabicyclo[5,4,0]undec-7-ene to give the pyrrolo[1,2-b]pyridazinederivative of general formula: ##STR24## in which B', R, R₁, R₂ and Tshave the same meaning as above.

The tosyl derivative of formula (23) is then hydrolysed in a basicmedium for instance aqueous alkali metal hydroxide, to provide therequired compound of formula (4).

3-Chloromethyl-pyridazine is a known compound having been published inKhim. Geterot. Sikl., Soedin. 3, pp. 412-414 (1970).

7) The compounds of formula (4) in which Cy represents a2-R-pyrazolo[1,5-a]pyrid-1-yl group can be prepared, in accordance withthe method described in European patent application No. 121,197, bytreating a 2-R-pyrazolo[1,5-a]pyridine with a halide of formula (9) inthe presence of a Friedel-Crafts catalyst such as for example aluminumchloride, to provide the 4-methoxyphenyl derivative of general formula:##STR25## in which B', R, R₁ and R₂ have the same meaning as above.

The pyrazolopyridine derivative of formula (24) is then demethylated forinstance by using pyridine hydrochloride at 200°-220° C. to provide therequired compound of formula (4).

8) The compounds of formula (4) in which Cy represents a phenyl groupcan be prepared by reacting benzene with a halide of formula (9) in thepresence of a Friedel-Crafts catalyst such as aluminum chloride, toprovide the required compound of formula (4).

9) The compounds of formula (4) in which Cy represents a 2-R-phenylgroup or a 1-R-2-naphthyl group can be prepared by treating a halide ofgeneral formula: ##STR26## in which B', R and Hal have the same meaningas above and R₇ and R₈ each represent hydrogen or are taken togetherwith the carbon atom to which they are attached to form a phenyl group,with a methoxyphenyl derivative of general formula: ##STR27## in whichR₁ and R₂ have the same meaning as above, in the presence of aFriedel-Crafts catalyst such as aluminum chloride, to obtain thecompounds of general formula: ##STR28## in which B', R, R₁ and R₂ havethe same meaning as above and R₇ and R₈ have the same meaning as informula (25).

The compounds of formula (27) are then demethylated using for instanceaqueous iodhydric acid to provide the required compound of formula (4).

Compounds of formula (25) are known products having been described inC.A. 81, 63285g, or can be obtained in accordance with known procedures.

Alternatively the compounds of formula (27) in which R₇ and R₇ are eachhydrogen and B' represents a --SO₂ -- group can be prepared by treatingthe alkali metal derivative of a 2-R-benzenesulphonate, with a phenylderivative of formula (26) in the presence of methanesulphonicacid/phosphorous pentoxide, in accordance with the method described inCommunications, April 1984, p. 323.

In accordance with another process, the compounds of formula (4) inwhich Cy represents a 2-naphthyl group and B' represents a --SO₂ --group can be obtained by reacting a 2-halogenosulphonyl naphthalene witha R₁ R₂ -phenol derivative. This sulphonate derivative is thenrearranged in the presence of aluminum chloride to obtain a complexwhich is treated by an acid such as hydrochloric acid to provide therequired compound of formula (4).

10) The compounds of formula (4) in which Cy represents an optionallymono- or di-substituted 2-R-4,5-dihydro-furan-3-yl group can be preparedby heating a ketone derivative of formula (18) with a1,2-dihalogenoethane of general formula: ##STR29## in which R₁₅ and R₁₆which are the same or different, each represent hydrogen, a lower alkylradical or a phenyl radical, in the presence of a basic agent such as analkali metal carbonate, to obtain a cyclopropane derivative of generalformula: ##STR30## in which B¹, R, R₁, R₂, R₁₅ and R₁₆ and Ts have thesame meaning as above.

The cyclopropane derivative of formula (29) is subsequently heatedbetween 100° and 130° C. in the presence of a phase transfer catalystsuch as for instance triphenylphosphine or tricaprylylmethyl ammoniumchloride to provide a 4-tosyloxyphenyl derivative of general formula:##STR31## in which B', R, R₁, R₂, R₁₅, R₁₆ and Ts have the same meansingas above and the said 4-tosyloxyphenyl derivative is then detosylated bytreatment with a basic agent such as an alkali metal hydroxide, toprovide the required compound of formula (4).

11) The compounds of formula (4) in which Cy represents an optionallymono- or di-substituted 2-R-furan-3-yl group can be obtained byoxidizing for instance with manganese oxide, a 4,5-dihydrofuranderivative of formula (30) to obtain a furan derivative of generalformula: ##STR32## in which B', R, R₁, R₂, R₁₅, R₁₆ and Ts have the samemeaning as above, which furan derivative is subsequently treated with abasic agent such as an alkali metal hydroxide, to obtain the requiredcompound of formula (4).

12) The compounds of formula (4) in which Cy represents a 2-R-furan-3-ylor 2-R-thien-3-yl or 2-R-pyrrol-3yl group can be prepared by reacting acompound of general formula: ##STR33## in which R has the same meaningas above and Q represents --O, --S or >N-R₁₁, with a halide of formula(9) and in the presence of a Friedel-Crafts catalyst such as aluminumchloride to obtain a 4-methoxy derivative of general formula: ##STR34##in which B', R, R₁, R₂ and Q have the same meaning as above, which issubsequently decarboxylated by heating and demethylated with anappropriate agent such as pyridine hydrochloride or aqueous hydrobromicacid, to provide the required compound of formula (4).

Alternatively, the compounds of formula (4) in which Cy represents anoptionally substituted 2-R-furan-3-yl group can be prepared byoxidizing, for instance with manganese oxide, a sulphide derivative offormula (30) to obtain an optionally substituted2-R-3-(4-tosyloxybenzenesulphonyl)furan derivative which is subsequentlytreated by a basic medium for instance an alkali metal hydroxide, toprovide the required compound of formula (4).

13) The compounds of formula (4) in which Cy represents a1-R-imidazol-2-yl or 1-R-benzimidazol-2-yl group can be obtained byreacting a 1-R-imidazole or 1-R-benzimidazole with a halide of formula(9) in the presence of a Friedel-Crafts catalyst such as aluminumchloride, to obtain a compound of general formula: ##STR35## in whichB', R, R₁ and R₂ have the same meaning as above, R₇ and R₈ eachrepresent hydrogen or are taken together with the carbon atoms to whichthey are attached to form a phenyl group which is subsequentlydemethylated using an ethanethiol/aluminum chloride mixture or2-mercaptoethanol in the presence of sodium hydride to obtain therequired compound of formula (4).

Compounds of formula (34) in which --OCH₃ is replaced by --O--Benzyl canalso be used. In such case the compounds of formula (34) in question aredebenzylated using for instance palladium charcoal for obtaining therequired compound of formula (4).

When R represents hydrogen, imidazole or benzimidazole is protected inthe 1-position with an appropriate N-protecting group for instance abenzyl group which can subsequently be removed, if desired, usingclassical procedures.

14) The compounds of formula (4) in which Cy represents an optionallysubstituted 5-R-isoxazol-4-yl derivative can be prepared by reacting anisoxazole derivative of general formula: ##STR36## in which B', R, R₁₅and Hal have the same meaning as above with a 4-methoxy derivative offormula (26) in the presence of a Friedel-Crafts catalyst such asaluminum chloride to obtain the compounds of general formula: ##STR37##in which B', R, R₁, R₂ and R₁₅ have the same meaning as above, which isdemethylated, using for instance aluminum chloride, to provide therequired compound of formula (4).

Compounds of formula (35) are known products having been described inGazz. Chim. Ital. 76, 30 (1946) while the other compounds of formula(35) can be obtained in accordance with the method described therein orclassical methods.

Alternatively, the compounds of formula (36) in which R₁₅ representshydrogen and B' represents a --SO₂ --group, can be obtained inaccordance with the method descrived in J. Hetero. Chem. 23, 1363 (1986)by reacting a 1-(4-methoxy-benzenesulphonyl)-2-N,N-dimethylaminoethenewith hydroxylamine.

Similarly, compounds of formula (36) in which B' represents a --SO₂ --group, R₁₅ is other than hydrogen and in which --OCH₃ is replaced by--O--Tosyl can be used for obtaining the corresponding compounds offormula (4). These 3-substituted-5-R-3-(4-O-Tosyl)-benzenesulphonylisoxazole derivatives can be prepared in accordance with the methoddescribed in Gazz. Chim. Ital. 98, 656 (1968) i.e. by reacting abenzenesulphonyl-ketone and an hydroxamic acid derivative.

15) The compounds of formula (4) in which Cy represents a5-R-pyrazol-4-yl group can be prepared by reacting a compound of generalformula: ##STR38## in which B', R, R₁, R₂ and Ts have the same meaningas above, with hydrazine, to obtain the required compound of formula(4).

The compounds of formula (37) are compounds which can be prepared inaccordance with J. Hetero. Chem., 23, 1363 (1986) i.e., from aN,N-dimethylaminoethene derivative and hydrazine.

Alternatively the compounds of formula (4) in which Cy represents a5-R-pyrazol-4-yl group can be directly obtained from a compound ofgeneral formula: ##STR39## in which R and Ts have the same meaning asabove, and hydrazine in excess. The compounds of formula (38) can beprepared in accordance with the method described in J. Hetero. Chem. 23,1363 (1986) cited above.

16) The compounds of formula (4) in which Cy represents a 1-R₁₁-2-R-indol-3-yl or 1-R₁₁ -3-R-indol-2-yl derivative can be prepared:

a) when R₁₁ represents hydrogen, by reacting p-methoxythiophenolsubstituted by R₁ and R₂ groups, with 2-R-indole or 3-R-indole in thepresence of iodine, to provide an indole derivative of general formula:##STR40## in which R, R₁ and R₂ have the same meaning as above, whichcan then be oxidized with 3-chloroperbenzoic acid to provide thesulphonyl derivatives of general formula: ##STR41## in which R, R₁ andR₂ have the same meaning as above.

The compounds of formulae (39) and (40) can subsequently be demethylatedusing 2-mercaptoethanol in the presence of sodium hydride to provide therequired compounds of formula (4); or

b) when R₁₁ is other than hydrogen, by treating a compound of formula(39) or (40) with an iodide of formula R₁₁ -l in which R₁₁ is other thanhydrogen and demethylating the 1-substituted derivative so obtained with2-mercaptoethanol in the presence of sodium hydride, to provide therequired compounds of formula (4).

17) The compounds of formula (4) in which Cy represents a 2-R-5-R₁₁-4,5,6,7-tetrahydro-thienol[3,2-c]pyrid-3-yl group and B' represents a--SO₂ -- group can be prepared by reacting a 2-R-5-R₁₁-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine in which R₁₁ is other thanhydrogen with a compound of general formula ##STR42## in which R₁, R₂, Mand Bz have the same meaning as above, in the presence ofmethanesulphonic acid/phosphorous pentoxide to obtain atetrahydrothienopyridine of general formula: ##STR43## in which R, R₁and R₂ have the same meaning as above and R₁₁ has the same meaning asabove with the exception of hydrogen.

The compounds of formula (42) are then hydrolysed in the presence of abasic agent such as an alkali metal hydroxide to provide the requiredcompounds of formula (4) in which R₁₁ is other than hydrogen.

Starting 2R-5-R₁₁ -4,5,6,7-tetrahydro-thieno[3,2-c]pyridines are knowncompounds having been described in Heterocycles, 22, 1235 (1984) or canbe prepared in accordance with the method described therein.

18) The compounds of formula (4) in which Cy represents a2-R-thieno[3,2-c]pyrid-3-yl group can be prepared by hydrolysing acompound of formula (42) in which R₁₁ represents a benzyl or halobenzylradical and further reacting the 4-hydroxybenzenesulphonyl derivative soobtained with palladium charcoal in diphenylether to provide therequired compound of formula (4).

19) The compounds of formula (4) in which Cy represents a5-R-thiazol-4-yl group can be prepared by demethylating a compound ofgeneral formula: ##STR44## in which B', R, R₁ and R₂ have the samemeaning as above, using hydrobromic acid in acetic acid, to provide therequired compounds of formula (4).

The compounds of formula (43) can be obtained in accordance with themethod described in Tetrah. Lett. 1972, p. 2777 i.e. from asulphonylmethylisocyanide and a thioglycolic acid derivative.

20) The compounds of formula (4) in which Cy represents a 1-R₁₁-5-R-imidazol-4-yl group can be obtained by demethylating with2-mercaptoethanol in the presence of sodium hydride, a compound ofgeneral formula: ##STR45## in which B', R, R₁, R₂ and R₁₁ have the samemeaning as above, to provide the required comounds of formula (4).

The compounds of formula (44) can be obtained in accordance with themethod described in Tetrahedron Lett. 23, pp. 2373-2374 (1972) i.e. froma sulphonylmethylisocyanide and an imidazol derivative.

21) The compounds of formula (4) in which B' represents a --SO₂ -- groupand Cy represents a group of formula (D) in which R₅ and R₆ are takentogether with the carbon atom to which they are attached to form anon-aromatic mono- or di-cyclic carbocyclic group having from 5 to 10carbon atoms and optionally substituted by a R group in the α-positionwith respect to the methyne group, for instance a 3-R-inden-2-yl,2-R-cyclohexen-1-yl or 1-R-3,4-dihydro-naphth-2-yl group can beprepared, in accordance with the method described J. Org. Chem. vol. 35,No. 12, pp. 4217-4222 (1970) by heating a compound of general formula:##STR46## in which R₅ and R₆ are taken together with the carbon atoms towhich they are attached to form a group having from 5 to 10 carbon atomsand optionally substituted by a R group in the α-position with respectto the methyne group, with a halide of 4-tosyloxybenzene substituted byR₁ and R₂ groups in an appropriate solvent such as benzene and in thepresence of anhydrous cupric chloride and triethylamine, to obtain a4-tosyloxyphenyl derivative of general formula: ##STR47## in which R₁,R₂ and Ts have the same meaning as above and R₅ and R₆ have the samemeaning as in formula (37) which is then detosylated using anappropriate agent such as an alkali metal hydroxide to obtain therequired compound of formula (4).

b) Compounds of formula (4) in which Cy represents a group (E).

The compounds of formula (4) in which Cy represents a 2-R-imidazol-1-ylor 2-R-benzimidazol-1-yl group can be obtained by reacting a2-R-imidazole or 2-R-benzimidazole with a halide of formula (9) in thepresence of a Friedel-Crafts catalyst such as aluminum chloride, toprovide a compound of general formula: ##STR48## in which B', R, R₁ andR₂ have the same meaning as above and R₇ and R₈ each represent hydrogenor are taken together with the carbon atoms to which they are attachedto form a phenyl group.

The compound of formula (47) is then demethylated using an appropriateagent for instance an ethanethiol/aluminum chloride mixture to give therequired compound of formula (4).

c) Compounds of formula (4) in which Cy represents a group (F).

The compounds of formula (4) in which Cy represents for instance a2-R-chromon-3-yl group and B' represents a --SO₂ -- group can beprepared by reacting a 2-R-3-halogeno-chromone with a 4-methoxyderivative of formula (9) in which B' represents a --SO₂ -- group, inthe presence of a Friedel-Crafts catalyst such as aluminum chloride, toobtain the chromone derivative of general formula: ##STR49## in which R,R₁ and R₂ have the same meaning as above, which is optionallydemethylated using for instance aqueous hydrobromic acid or pyridinehydrochloride, to provide the required compound of formula (4).

d) Compounds of formula (4) in which Cy represents a group (G)

The compounds of formula (4) in which Cy represents an optionallysubstituted 5-R-2,3-dihydro-furan-2-one-4-yl can be prepared byreacting, in basic medium, for instance potassium carbonate, a ketone offormula (18) with a 2-halogenoacetate of general formula: ##STR50## inwhich Hal, R₁₄ and R₁₅ have the same meaning as above, to obtain aketoester which is first hydrolysed in basic medium and then treatedwith a strong acid to provide the carboxylic acid derivative of generalformula: ##STR51## in which B', R, R₁, R₂ and R₁₄ have the same meaningas above.

The acid of formula (50) when treated with trifluoroacetic acid orthionyl chloride provides the required compound of formula (4).

e) Compounds of formula (4) in which Cy represents a group (H)

The compounds of formula (4) in which Cy represents an optionallysubstituted 5-R-1,3-dihydro-2H-imidazol-2-one-4-yl can be obtained byreacting a 5-R-imidazol-2-one with a halide of formula (9) to obtain acompound of general formula: ##STR52## in which R, R₁, R₂, R₁₂, R₁₃ andB' have the same meaning as above which is subsequently demethylatedusing appropriate procedures such as in the presence of iodhydric acid,pyridine hydrochloride or hydrobromic acid, to obtain the requiredcompound of formula (4).

As an alternative procedure, the compounds of formula (4) in questioncan be prepared by adapting the method similar to that described in J.Am. Chem. Soc. 68, p. 2350 (1946).

According to an alternative method, the compounds of formula (1) inwhich B represents a --S-- or --SO₂ -- group and A represents analkylene radical, preferably those in which A represents a propyleneradical, can also be obtained by reacting, in the presence of a basicagent such as an alkali metal carbonate, for example potassiumcarbonate, an alkali metal hydroxide such as sodium or potassiumhydroxide, an alkali metal hydride such as sodium hydride or an alkalimetal alcoholate, for example sodium methylate or ethylate, a4-hydroxyphenyl derivative of formula (4) above with a compound ofgeneral formula: ##STR53## in which X has the same meaning as above andpreferably represents chlorine or a benzenesulphonyloxy orp-toluenesulphonyloxy radical, A represents an alkylene radical and R₃and R₄ have the same meaning as above, the reaction taking place at atemperature between room-temperature and the refluxing temperature ofthe medium and in a polar solvent such as methyl ethyl ketone ordimethylsulphoxide to form the desired aminoalkoxyphenyl derivative offormula (1) in the form of the free base.

When R₄ represents hydrogen, the nitrogen atom is preferably protectedby a labile group for instance a protecting group which can beeliminated in basic medium for example the tertiobutoxycarbonyl (BOC)group.

The compounds of formula (52) are products which are known or which canbe prepared by known methods.

The compounds of formula (1) in which Cy represents a group (E), Arepresents an alkylene chain and B represents a --S-- or SO₂ -- groupcan also be prepared by reacting a 2-R-imidazole or 2-R-benzimidazolewith a halide of general formula: ##STR54## in which B', R₁, R₂, Hal andX have the same meaning as above and A represents an alkylene chain, inthe presence of an acid acceptor such as triethylamine to obtain acompound of general formula: ##STR55## in which B', R, R₁, R₂ and X havethe same meaning as above, R₇ and R₈ each represent hydrogen or aretaken together with the carbon atom to which they are attached to form aphenyl group and A represents an alkylene chain, which compound issubsequently reacted with an amine of formula (3) to obtain the requiredcompound of formula (1) in the form of a free base.

Similarly, the compounds of formula (1) in which Cy represents anoptionally mono- or di-substituted 2-R-4,5-dihydro-furan-3-yl group, Arepresents an alkylene chain and B represents a --S-- or --SO₂ -- group,can be prepared by hydrolysing a cyclopropane derivative of formula (29)in the presence of an aqueous alkali metal hydroxide solution to providea 4-methoxyphenyl derivative of general formula: ##STR56## in which B',R, R₁, R₂, R₁₅ and R₁₆ have the same meaning as above, which is thenreacted:

with a dihaloalkane of formula (5) and the resulting product with anamine of formula (3); or

with a compound of general formula (52), to provide an aminoalkoxyphenylderivative of general formula: ##STR57## in which B', R, R₁, R₂, R₃, R₄,R₁₅ and R₁₆ have the same meaning as above and A represents an alkylenechain.

The cyclopropane derivative of formula (56) is subsequently heatedbetween 100° and 130° C. in the presence of a phase transfer catalystsuch as for instance triphenylphosphine or tricaprylylmethyl ammoniumchloride to provide the required 2,3-dihydrofuran derivative of formula(1) in the form of a free base.

II. When B represents a --SO-- group, by treating, with an oxidizingagent, a sulphide of formula (1) in which B represents a --S-- group,this compound of formula (1) being in the form of the free base of asalt thereof so as to obtain the required compound in the form of thefree base or a salt thereof.

Where the required compound is provided in the form of a salt, the freebase thereof can be recovered by treatment with a basic agent such as analkali metal carbonate for example potassium carbonate or an alkalimetal bicarbonate for example sodium bicarbonate.

Generally, the reaction takes place in water or in an organic solventsuch as methylene chloride and in the presence of a suitable oxidizingagent such as for example sodium periodate, potassium permanganate or3-chloroperbenzoic acid.

Depending on the oxidizing agent used, mixtures of sulphoxides orsulphones can be obtained. These mixtures can be separated byconventional procedures for instance by chromatography.

III. When B represents a --S-- or --SO₂ -- group and A represents anoptionally substituted 2-hydroxy-propylene chain, by reacting underreflux a 4-hydroxyphenyl derivative of formula (4) with anepihalohydrin, such as epichlorhydrin or epibromhydrin in dextrorotatoryor leavorotatory form or in the form of a mixture of these isomers, forexample in racemic form, and in the presence of a basic agent such as analkali metal carbonate, for example potassium carbonate, an alkali metalhydroxide, for example sodium or potassium hydroxide, an alkali metalhydride such as sodium hydride or an alkali metal alcoholate, forexample sodium methylate or ethylate, and in a polar solvent such asmethyl ethyl ketone to give the oxyranylmethoxy derivatives of generalformula: ##STR58## in which Cy, B', R₁ and R₂ have the same meaning asabove.

The oxyranylmethoxy derivatives of formula (57) are then treated underreflux with an amine of formula (3), this being performed in a polarsolvent such as methyl ethyl ketone or in an excess of amine of formula(3) to give the desired compound of formula (1) in the form of the freebase in which A represents a 2-hydroxypropylene chain which can bereacted, if desired, with a lower alkyl halide in the presence of astrong basde to provide the compound of formula (1) in the form of thefree base in which A represents a 2-hydroxypropylene chain in which thehydroxy is substituted by a lower alkyl radical.

In some cases, by-products may be formed in parallel with the compoundsof formula (57) above, on this case4-(3-halo-2-hydroxypropoxy)benzenesulphonyl derivatives.

On reaction with the amine of formula (3), these derivatives willnevertheless give rise to the desired compounds of formula (7) in whichA represents a 2-hydroxypropylene chain.

The compounds of formula (1) thereby obtained in the form of the freebase can then be converted to pharmaceutically acceptable salts byreaction with a suitable organic or inorganic acid, for example oxalic,maleic, fumaric, methanesulphonic, benzoic, ascorbic, pamoic, succinic,hexamic, bismethylenesalicylic, ethanedisulphonic, acetic, propionic,tartaric, salicylic, citric, gluconic, lactic, malic, cinnamic, madelic,citraconic, aspartic, palmitic, stearic, itaconic, glycolic,p-aminobenzoic, glutamic, benzenesulphonic or theophyllineacetic acid orwith lysine or histidine.

Similarly, the N-oxide derivatives of the compounds of formula (1) canbe formed by oxidizing the compound of formula (1) in question with anappropriate oxidizing agent for instance hydrogen peroxide or3-chloroperbenzoic acid.

Monoalkyl- or dialkylaminoalkoxybenzenesulphonyl-benzofuran orbenzothiophene derivatives are reported in U.S. Pat. No. 4,117,128 aspresenting pharmacological effects in the cardiovascular field.

In the course of the elaboration of the present invention, tests werecarried out with compounds specifically cited in the aforesaid U.S.patent, more particularly with 2-ethyl- or2-n-butyl-3-[4-(2-diethylaminoethoxy)benzenesulphonyl]benzofuran.

From results of these tests, it could be concluded that in the dog atthe dose of 10 mg/kg by intravenous route, these known compounds onlypresent a weak α-antiadrenergic activity and no or practically noβ-antiadrenergic effect.

It has now been surprisingly discovered, in the context of the presentinvention, that by replacing the mono- or di-alkylaminoalkoxy chain ofthe benzenesulphonyl-benzofurans or benzothiophenes of the prior art byan aralkylaminoalkoxy chain, compounds are obtained which show muchgreater α-and β-antiadrenergic activities than those of the knowncompounds in question.

For instance, aralkylaminoalkoxybenzenesulphonyl-benzofurans orbenzothiophenes in question have shown, at doses as low as 0.1 to 1.5mg/kg, sub-total inhibition of the α-adrenergic effect together with animportant β-antiadrenergic action.

Such very valuable antiadrenergic properties were also found to bepresent in compounds similar in structure to thearalkylaminoalkoxybenzenesulphonylbenzofurans and benzothiophenes inquestion but in which the benzofuran or benzothiophene moiety isreplaced by another carbocyclic or heterocyclic group.

Therefore, one class of compounds of the invention relates to thosecompounds of formula (1) and the pharmaceutically acceptable salts orN-oxide thereof, in which Cy, R₁, R₂, R₄ and A have the same meaning asformula (1), B represents a --SO₂ -- group and R₃ represents a radical--Alk--Ar.

A particularly valuable class of compounds of the invention are those inwhich R₁, R₂, R₄ and A have the same meaning as in formula I, Brepresents a --SO₂ -- group, R₃ represents a radical --Alk--Ar, Cyrepresents a group selected from:

indolizin-3-yl

benzofuryl or benzothienyl more particularly 2-R-benzofur-3-yl and2-R-benzothien-3-yl

quinolinyl such as 2-R-quinolin-3-yl

pyrrolo[1,2-b]pyridazinyl more particularly6-R-pyrrolo[1,2-b]pyridazin-5-yl

pyrazolo[1,5-a]pyridyl more particularly 2-R-pyrazolo[1,5-a]pyrid-3-yl

imidazo[1,2-a]pyridyl more particularly 2-R-imidazo[1,2-a]pyrid-3-yl

4,5-dihydrofuranyl more particularly 2-R-3,4-dihydrofuran-3-yl

phenyl more particularly 2-R-phenyl

naphthyl more particularly 2-R-1-naphthyl

indolyl more particularly 2-R-indol-3-yl or 1-R₁₁ -2-R-indol-3-yl group.

Similarly indolizine derivatives which are substituted in the 1-positionwith an alkoxybenzoyl chain which is itself substituted with a mono- ordi-alkylamino group, and which are stated to have pharmacologicaleffects in the cardiovascular field, are already known.

In this connection, there may be mentioned French Patent No. 2,341,578and Eur. J. Med. Chem. 1977, 12, No. 4, pp. 345-350, which specificallydescribe 2-ethyl-, 2-n-propyl- or 2-n-butyl-1-[4-(3-di-n-propyl- or3-di-n-butylaminopropoxy)benzoyl]indolizine optionally dimethylated onthe benzoyl radical.

These known compounds showed antiadrenergic activities which werenonexistent or low, at all events too low to be of any value fortherapy.

Other monoalkyl- or dialkyl-aminoalkoxybenzoyl derivatives are alsoknown.

For instance are reported in the literature monoalkyl- ordialkyl-aminoalkoxybenzoyl derivatives of:

thiophene [(J. Med. Chem. V, 13 (3) pp. 359-366 (1970)]

naphthalene or dihydronaphthalene (Chim. Ther. V, 7 (5) pp. 369-377)

pyridine (Ing. Chim. V, 59 (283) pp. 3-13 (1977)]

thieno [3,2-c]pyridine [Heterocycles, V, 22 (5), pp. 1235-1247 (1984)]

indole [Eur. J. Med. Chem.-Chim. Ther. V. 12 (5) pp. 483-487 (1977)]

furan (French Patent No. 2,400,515)

chromone (U.S. Pat. No. 4,220,645).

Tests carried out with these known compounds showed that some of thempresented antiadrenergic activities but which were low, at all eventstoo low to be of any value for therapy.

It has now been found, in addition, that mono- or di-alkylaminoalkoxybenzenesulphonyl derivatives resembling those described in U.S. Pat. No.4,117,128 but in which the benzofuran or benzothiophene moiety has beenreplaced by another carbocyclic or heterocyclic ring present morevaluable antiadrenergic properties than known sulphonyl derivatives ofthe aforesaid U.S. patent or known derivatives of the above-citedreferences.

For instance, α- and β-antiadrenergic properties were registered, in thedog by intravenous route at doses as low as 0.1 to 1.5 mg/kg withrespect to mono- or di-alkylaminoalkoxybenzenesulphonyl derivatives offormula (1) in which Cy represents another group than benzofuryl orbenzothienyl for instance a quinolinyl or pyrrolo[1,2-b]pyridazinylmoiety.

Yet, another valuable class of compounds of the invention are those inwhich R₁, R₂, R₄ and A have the same meaning as in formula (1), Brepresents a --SO₂ -- group and R₃ represents an alkyl radical with theproviso that Cy is different from benzo[b]furyl or benzo[b]thienyl.

A particularly valuable class of compounds of the invention are those inwhich R₁, R₂, R₄ and A have the same meaning as in formula (1), Brepresents a --SO₂ -- group, R₃ represent an alkyl radical and Cyrepresents a group selected from:

quinolinyl more particularly 2-R-quinolin-3-yl

pyrrolo[1,2-b]pyridazinyl more particularly6-R-pyrrolo[1,2-b]pyridazin-5-yl.

pyrazolo[1,5-a]pyridyl more particularly 2-R-pyrazolo[1,5-a]pyrid-3-yl.

imidazo[1,2-a]pyridyl more particularly 2-R-imidazo[1,2-a]pyrid-3-yl.

4,5-dihydrofuranyl more particularly 2-R-4,5-dihydrofuran-3-yl group.

indolyl more particularly 2-R-indol-3-yl and 1-R₁₁ -2-R-indol-3-yl.

indolizin-3-yl.

Moreover, it has been found that the calcium inhibitory activity of thecompounds of the invention is at least equal to, if not greater than,that observed in tests performed with the known compounds. In contrastto the known compounds, it has thus been possible to demonstrate for thecompounds of the present invention a pharmacological spectrum revealinganticalcium and α- and β-antiadrenergic compounds with a balancedintensity which is of therapeutic value, for example, for treatment ofangina.

As has been reported in detail by R. Charlier in "Bruxelles Medical",No. 9, September 1969, pages 543-560, it is accepted that an antianginaldrug treatment should be capable, in particular, of antagonizing theantiadrenergic type cardiovascular reactions. To this end, agentscapable of blocking the α-receptors have been proposed.

However, the clinical application of such compounds to the treatment ofangina remained unsuccessful, very probably due to the fact thatα-receptor antagonists include only a very partial neutralization of theadrenergic system, the activity of the β-receptors being unaffected.

In fact, the most undesirable haemodynamic manifestations which occur inangina pectoris patients during their painful attacks are, most of all,cardiac, and consequently involve the β-receptors.

In parallel, treatments have been proposed with drugs which areβ-adrenergic receptor antagonists. These compounds, which are of genuineclinical value, decrease the attacks of angina by reducing the work ofthe heart by slowing the heart rate. However, there is no fall in theperipheral arterial resistance which, on the contrary, rises thorughrelease of the α-tonicity.

These drug treatments nevertheless modify some haemodynamic parametersin a direction which, at a fundamental level, detracts from the value ofthese drugs for angina pectoris patients in particular and heartpatients in general.

If the antiadrenergic aspect of β-blockers is considered, it becomesclear that only the tachycardia and the increase in the force and thespeed of contraction of the heart are capable of being neutralized, thearterial hypertension involving a stimulation of the α-receptors onwhich β-antagonists have no action.

In fact, while the cardiovascular disturbances brought about by thestimulation of the β-receptors are the more harmful to angina patients,it is nonetheless true that arterial hypertension also plays a notinsignificant part.

In addition, blocking the β-receptors involves a risk, depriving thepatient suffering from cardiac insufficiency of a compensatory mechanismwhich he normally brings into play to limit his circulatoryinsufficiency.

This reflex mechanism, the main component of which makes use of thepathway of the β-adrenergic system, leads, in particular, to an increasein the force and the speed of contraction of the heart. In consequence,if this system is blocked, the patient suffering from cardiacinsufficiency experiences a worsening of his functional breakdown. It ishence logical to consider that the use of a β-blocker whose action ispure and complete will always involve a cardiac risk.

It hence appears to be desirable not to seek complete α- orβ-antagonistic properties, given the clinical side effects that thesecan bring about. It seems more logical to aim to subdue rather than toeliminate the cardiovascular disturbances which characterize thehyperstimulation of the adrenergic system as a whole.

The compounds of the invention meet this objective since they showincomplete α- and β-type antiadrenergic properties. They can hence beconsidered, not as β-blockers but as adreno-decelerators, that is to saypartial antagonists of the α- and β-adrenergic reactions, potentiallydevoid of the disadvantages listed above for β-blockers.

In addition, the calcium inhibitory component demonstrated in thecompounds of the invention will act as an exceptional complement to thepharmacological spectrum of their cardiovascular action.

It is known, in effect, that the transport of calcium ions is one of themain components of the action potential in heart cells and, inconsequence, this transport plays a fundamental part in the electricalconduction as well as in the disorders which may occur therein(arrhythmia). In addition, it is known that calcium ions are involved inthe excitation-contraction coupling which controls the degree ofvasoconstriction in smooth muscle and, in the same circumstances, playsa critical part in attacks of angina pectoris.

Compounds which are calcium antagonists act at the level of the cellmembrane by selectively preventing calcium from participating in theprocess of contraction within the arterial cell.

In fact, it appears increasingly clear, at the present time, that theclinical results provided by the combination of calcium inhibitors andβ-adrenergic inhibitors are better than when each inhibitor is usedseparately (J.A.M.A. 1982, 247, pages 1911-1917).

It appears, moreover, that no β-blocker which exerts, in addition, asignificant inhibitory action in respect of calcium transport exists atthe present time.

From this standpoint, the compounds of the invention possessing both ananticalcium component and an α- and β-antiadrenergic component will beof fundamental value, since they are capable of more extensivetherapeutic applications than a separate β-blocker or a separate calciuminhibitor.

Compounds of the invention possess an α- and β-antiadrenergic componentreinforced by an oxygen-economizing effect capable of providing atherapeutic effect in man in the syndrome of angina of effort, whichcan, moreover, be treated by traditional β-blockers. However, the majoradvantage of these compounds will reside in the fact that they may, as aresult of their anti-calcium effect, be used in the treatment of anginaat rest, a syndrome induced by the appearance of a spasm in the coronaryarteries, which is combated at present by compounds such as diltiazem,verapamil or nifedipine.

In addition, compounds of the invention were also shown to be capable ofinducing a substantial increase in the coronary flow.

The results of pharmacological tests performed for the purpose ofdetermining the cardiovascular properties of the compounds of theinvention are recorded below.

I. Calcium inhibitory properties

The properties of inhibiting calcium transport at the membrane levelshown by the compounds of the invention were demonstrated by measuringtheir antagonistic action with respect to the contractile response topotassium-induced depolarization on isolated rat aorta. It is wellestablished that the depolarization of a smooth muscle membrane bypotassium renders the latter permeable to extracellular calcium andinduces muscle contraction.

Consequently, the measurement of the inhibition of the contractileresponse to depolarization by potassium, or the measurement of arelaxation of the tonic contraction on potassium depolarization, canrepresent an evaluation of the power of a compound as an inhibitor ofthe membrane permeability to Ca⁺⁺ ions.

The technique used was as follows:

The aorta was removed from male Wistar rats weighing approximately 300g, and cut into strips approximately 40 mm long and 3 mm wide.

These fragments were placed in a 25-ml isolated organ trough containinga modified Krebs-bicarbonate solution (112 mM NaCl; 5 mM KCl; 25 mMNaHCO₃ ; 1 mM KH₂ PO₄ ; 1.2 mM mgSO₄ ; 2.5 mM CACl₂ ; 11.5 mM glucose,distilled water to 1000 ml) through which a stream of 5-7% carbondioxide in oxygen was passed, and maintained at 37° C. The preparationwas connected to a force microsensor and the contractile responserecorded after amplification on a recorder.

A tension of 2 g was applied to the preparation. This tension wasmaintained for 60 minutes in the modified Krebs-bicarbonate solution,and contractions were then induced by replacing the Krebs-bicarbonatesolution by a potassium-Krebs solution (17 mM NaCl; 100 mM KCl; 25 mMNaHCO₃ ; 1 mM KH₂ PO₄ ; 1.2 mM MgSO₄ ; 2.5 mM CaCl₂ ; 11.5 mM glucose,distilled water to 1000 ml). When the contractile response of thepreparation had become reproducible, a given amount of a compound of theinvention was introduced into the bath. Sixty minutes later, a new spasmwas induced by potassium depolarization.

The results obtained on the aorta used in the experiment were thenexpressed as a percentage of the maximum contractional effect beforeincubation with the test substance.

By way of examples, the results which follow were obtained, thecompounds of formula (1) being in the form of the base, hydrochloride oroxalate.

    __________________________________________________________________________     ##STR59##                                                                                                                   % of the maximum               Com-                                           contractional effect           pound                                                                             Cy                     Am                  10.sup.-6 M                                                                       10.sup.-7 M                                                                       10.sup.-8 M                                                                       10.sup.-9          __________________________________________________________________________                                                               M                  Ex. 20                                                                             ##STR60##             N(n-C.sub.4 H.sub.9).sub.2                                                                        22.4                                                                              67.3                       Ex. 21                                                                             ##STR61##                                                                                            ##STR62##          3.7 54  89.7                   Ex. 16                                                                             ##STR63##             N(n-C.sub.4 H.sub.9).sub.2                                                                        0   18.9                                                                              83                     Ex. 17                                                                             ##STR64##                                                                                            ##STR65##          0   15.1                                                                              67.1                                                                              84.9               Ex. 18                                                                             ##STR66##             NHC(CH.sub.3).sub.3 13.2                                                                              66.5                                                                              84                     Ex. 22                                                                             ##STR67##                                                                                            ##STR68##              0   18.1                                                                              68.1               Ex. 9                                                                              ##STR69##                                                                                            ##STR70##          21.4                                                                              73.7                       Ex. 10                                                                             ##STR71##             N(n-C.sub.4 H.sub.9).sub.2                                                                        32.4                                                                              85.3                       Ex. 11                                                                             ##STR72##             N(n-C.sub.4 H.sub.9).sub.2                                                                        47.5                                                                              64.8                       Ex. 1                                                                              ##STR73##                                                                                            ##STR74##              9.5 34.1                                                                              68.7               Ex. 12                                                                             ##STR75##                                                                                            ##STR76##          2.6 19.7                                                                              60.4                                                                              81.7               Ex. 13                                                                             ##STR77##                                                                                            ##STR78##          9.3 38.3                                                                              80.9                   Ex. 14                                                                             ##STR79##                                                                                            ##STR80##          9.7 45.3                                                                              68.9                   Ex. 15                                                                             ##STR81##                                                                                            ##STR82##          36.8                                                                              59  76                     Ex. 19                                                                             ##STR83##                                                                                            ##STR84##          8.2 66.7                                                                              78.3                   Ex. 23                                                                             ##STR85##                                                                                            ##STR86##              43.2                                                                              86  89.8               Ex. 24                                                                             ##STR87##             N(n-C.sub.4 H.sub.9).sub.2                                                                        4.0 59.4                                                                              90.3                   Ex. 25                                                                             ##STR88##             NHC(CH.sub.3).sub.3 10.3                                                                              77.9                                                                              94.3                   Ex. 60                                                                             ##STR89##                                                                                            ##STR90##          3.7 21.7                                                                              59.3                                                                              93.3               Ex. 61                                                                             ##STR91##             N(n-C.sub.4 H.sub.9).sub.2                                                                            43.2    89.1               Ex. 49                                                                             ##STR92##                                                                                            ##STR93##          16.8                                                                              62.8                                                                              83.3                   Ex. 63                                                                             ##STR94##             N(n-C.sub.4 H.sub.9).sub.2                                                                        4.2 43.4                                                                              85.1                   Ex. 55                                                                             ##STR95##                                                                                            ##STR96##          0   5.1 34.5                                                                              71.4               Ex. 52                                                                             ##STR97##             N(n-C.sub.4 H.sub.9).sub.2                                                                        4.9 37.4                                                                              66.0                   Ex. 56                                                                             ##STR98##             N(n-C.sub.4 H.sub.9).sub.2                                                                        0   15.1                                                                              71.0                                                                              84.6               Ex. 34                                                                             ##STR99##                                                                                            ##STR100##         8.7 11.2                                                                              61.9                                                                              87.0               Ex. 36                                                                             ##STR101##                                                                                           ##STR102##         0   21.3                                                                              56.9                   Ex. 66                                                                             ##STR103##                                                                                           ##STR104##         59.8                                                                              68.7                                                                              91.4                   Ex. 70                                                                             ##STR105##            N(n-C.sub.4 H.sub.9).sub.2                                                                        13.7                                                                              66.7                                                                              90.6                   Ex. 72                                                                             ##STR106##            N(n-C.sub.4 H.sub.9).sub.2                                                                        10.0                                                                              38.7                                                                              75.8                   Ex. 41                                                                             ##STR107##                                                                                           ##STR108##         13.6                                                                              50.6                                                                              81.4                   Ex. 67                                                                             ##STR109##            N(n-C.sub.4 H.sub.9).sub.2                                                                        66.2                                                                              77.5                                                                              85.7                   Ex. 57                                                                             ##STR110##                                                                                           ##STR111##             11.8                                                                              25.0                                                                              81.8               Ex. 58                                                                             ##STR112##            NHC(CH.sub.3).sub.3 8.1 51.7                                                                              84.5                   Ex. 69                                                                             ##STR113##            N(n-C.sub.4 H.sub.9).sub.2                                                                        5.8 16.8                                                                              54.6                                                                              75.3               Ex. 68                                                                             ##STR114##            NHC(CH.sub.3).sub.3 5.4 28.1                                                                              76.1                                                                              92.5               Ex. 64                                                                             ##STR115##            NHC(CH.sub.3).sub.3 2.7 52.2                                                                              92.3                   Ex. 62                                                                             ##STR116##                                                                                           ##STR117##             6.0 66.1                                                                              84.8               Ex. 51                                                                             ##STR118##                                                                                           ##STR119##             11.9                                                                              62.9                                                                              83.6               Ex. 59                                                                             ##STR120##                                                                                           ##STR121##                 41.1                   __________________________________________________________________________     ##STR122##                                                                                                                  % of the maximum               Com-                                           contractional effect           pound                                                                             Cy                   n Am                  10.sup.-6 M                                                                       10.sup.-7 M                                                                       10.sup.-8 M                                                                       10.sup.-9          __________________________________________________________________________                                                               M                  Ex. 35                                                                             ##STR123##          2                                                                                ##STR124##             4.7 53.3                                                                              83.9               Ex. 37                                                                             ##STR125##          2                                                                                ##STR126##             11.1                                                                              53.9                   Ex. 38                                                                             ##STR127##          4                                                                                ##STR128##         3.8 31.5                                                                              61.0                                                                              80.8               Ex. 39                                                                             ##STR129##          4                                                                                ##STR130##             33.6                                                                              53.1                   __________________________________________________________________________     ##STR131##                                                                                                                   % of the maximum                                                              contractional effect          Comp.                                                                             Cy               B'    Am                   10.sup.-5 M                                                                        10.sup.-6 M                                                                        10.sup.-7           __________________________________________________________________________                                                              M                   Ex. 5                                                                              ##STR132##      SO.sub.2                                                                             ##STR133##          33.3 81.7 87.5                Ex. 4                                                                              ##STR134##      SO.sub.2                                                                            N(n-C.sub.4 H.sub.9)N                                                                              37   84.7 88.9                Ex. 8                                                                              ##STR135##      SO.sub.2                                                                            NHC(CH.sub.3).sub.3  70.6 87.1                     Ex. 6                                                                              ##STR136##      SO.sub.2                                                                            N(n-C.sub.4 H.sub.9).sub.2                                                                         20.2 75.5 89.7                Ex. 7                                                                              ##STR137##      SO.sub.2                                                                             ##STR138##          14   70.7 88                  Ex. 2                                                                              ##STR139##      S     N (n-C.sub.4 H.sub.9).sub.2                                                                        2.6  58   86.2                Ex. 3                                                                              ##STR140##      S                                                                                    ##STR141##          3.1  59   85                  Ex. 26                                                                             ##STR142##      S                                                                                    ##STR143##          3.0  64.2 85.4                Ex. 28                                                                             ##STR144##      SO.sub.2                                                                             ##STR145##          19.2 73.1 86.6                Ex. 27                                                                             ##STR146##      S                                                                                    ##STR147##          6.7  55.0 90.2                Ex. 21                                                                             ##STR148##      SO.sub.2                                                                             ##STR149##               26.9 79.6                Ex. 73                                                                             ##STR150##      SO.sub.2                                                                            N(n-C.sub.4 H.sub.9).sub.2                                                                              50.7 86.2                Ex. 43                                                                             ##STR151##      SO.sub.2                                                                             ##STR152##          23.5 66.7 87.5                Ex. 42                                                                             ##STR153##      SO.sub.2                                                                             ##STR154##          65.8 92.4 87.3                Ex. 46                                                                             ##STR155##      SO.sub.2                                                                             ##STR156##          15.1 62.5 87.6                Ex. 65                                                                             ##STR157##      SO.sub.2                                                                            NHC(CH.sub.3).sub.3       32.0 83.3                Ex. 71                                                                             ##STR158##      SO.sub.2                                                                            N(n-C.sub.4 H.sub.9).sub.2                                                                         38.6 79.3 90.4                Ex. 26                                                                             ##STR159##      SO.sub.2                                                                             ##STR160##          19.2 73.1 86.6                __________________________________________________________________________

By way of comparison, the following results were obtained with knowncompounds:

    __________________________________________________________________________     ##STR161##                                                                                  % of the maximum                                                              contractional effect                                           Compound  R    10.sup.-6 M                                                                            10.sup.-7 M                                                                       10.sup.-8 M                                       __________________________________________________________________________    A         n-C.sub.4 H.sub.9                                                                  25       60.3                                                                              84.3                                              B         C.sub.2 H.sub.5                                                                    52.2     84.9                                                  __________________________________________________________________________     ##STR162##                                                                                              % of the maximum                                                              contractional effect                               Compound                                                                              R    R.sub.1                                                                         R.sub.2                                                                          Am       10.sup.-6 M                                                                        10.sup.-7 M                                   __________________________________________________________________________    Compound C                                                                            n-C.sub.4 H.sub.9                                                                 H  H  N(n-C.sub.4 H.sub.9).sub.2                                                             25.0 74.4                                          Compound D                                                                            C.sub.2 H.sub.5                                                                   CH.sub.3                                                                         CH.sub.3                                                                         N(n-C.sub.4 H.sub.9).sub.2                                                             19.3 64.7                                          Compound E                                                                            C.sub.2 H.sub.5                                                                   H  H  N(n-C.sub.3 H.sub.7).sub.2                                                             37.9 89.1                                          __________________________________________________________________________

II. Antiadrenergic properties

The object of this test is to determine the capacity of the compounds ofthe invention for reducing the increase in epinephrine-induced increasein blood pressure (anti-α effect) and the isoprenaline-inducedacceleration in heart rate (anti-β effect), in dogs previouslyanaesthatized with pentobarbital and atropinized.

For each dog, the dose of epinephrine (between 3 and 10 μg/kg) whichinduced a reproducible increase in the blood-pressure of approximately133×10² Pa and the dose of isoprenaline (1 to 2 μg/kg) which induced areproducible increase in the heart rate of approximately 70 beats/min.were first determined. The dose of epinephrine and of isoprenaline,determined in this manner, were injected alternately every ten minutesand, after two successive reference responses had been obtained, anamount of the test compound was administered intravenously.

Anti-α effect

The percentage reduction in the hypertension induced by the testcompound compared with the reference hypertension previously obtained(approximately 100 mm Hg) was recorded.

Anti-β effect

The percentage reduction in the acceleration of the heart rate inducedby the test compound compared with the reference tachycardia measuredpreviously (approximately 70 beats) was recorded.

In both cases, the results of the reduction in blood-pressure or in theheart rate have been expressed as follows:

+for a reduction<50%

++for a reduction≧50%

+++for a reduction sub-total (almost complete reduction).

The following results were recorded:

    ______________________________________                                        Ex. 1   0.13         + + +       + +                                          Ex. 5   11.2         + +         + +                                          Ex. 9   10.1         + + +       + +                                          Ex. 10  4.9          +           + +                                          Ex. 11  5.89         + +         + +                                          Ex. 12  0.1          + + +       +                                            Ex. 13  1.3          + + +       +                                            Ex. 14  0.6          + + +       + +                                          Ex. 15  1.2          + + +       + +                                          Ex. 16  0.12         + +         +                                            Ex. 17  0.13         + + +       + +                                          Ex. 18  0.52         + +         +                                            Ex. 19  3            + + +       + +                                          Ex. 20  1.2          + + +       +                                            Ex. 21  1.3          + + +       +                                            Ex. 22  0.13         + +  +      +                                            Ex. 23  3            + + +       + +                                          Ex. 60  0.12         + + +       + + +                                        ______________________________________                                    

By way of comparison, the known compounds showed the followingantiadrenergic effects:

    ______________________________________                                                                  anti-α                                                                            anti-β                               Compound    Dose (mg/kg)  effect    effect                                    ______________________________________                                        Compound A  10            +         0                                         Compound B  10            + + +     +                                         Compound C  10            +         0                                         Compound D  10            +         +                                         Compound E  10            +         + +                                       Compound F* 10            -         0                                         ______________________________________                                         * = 2ethyl-1-{4-[3-(di-n-butylamino-propyloxy]benzoyl}-indolizine.       

These results demonstrate that the compounds of the invention show muchgreater α- and β-antiadrenergic activity than those of the compounds ofthe prior art.

The therapeutic compositions according to the invention can be presentedin any form suitable for administration in human or veterinary therapy.As regards the administration unit, this can take the form of, forexample, a coated- or uncoated tablet, hard- or soft-gelatin capsule,packaged powder, suspension or syrup for oral administration, asuppository for rectal administration or a solution or suspension forparenteral administration.

The therapeutic compositions of the invention may contain, peradministration unit, for example, from 50 to 500 mg as the weight ofactive ingredient for oral administration, from 50 to 200 mg of activeingredient for rectal administration and from 50 to 150 mg of activeingredient for parenteral administration.

Depending on the administration route chosen, the therapeuticalveterinary compositions of the invention will be prepared by combiningat least one of the compounds of formula (1), or a non-toxic additionsalt of this compound, with a suitable excipient, it being possible forthe latter to consist, for example, of at least one ingredient selectedfrom the following substances: lactose, starches, talc, magnesium,stearate, polyvinylpyrrolidone, alginic acid, colloidal silica,distilled water, benzyl alcohol or sweetening agents.

The following non-limiting examples illustrate the invention:

EXAMPLE 1 Preparation of2-isopropyl-3-[4-{3-[N-methyl-N-(3,4-dimethoxy-β-phenethyl)amino]propyloxy}benzenesulphonyl]indolizine oxalate (SR 33770 A)

a) 1-Ethoxycarbonyl-2-isopropyl-3-(4-methoxybenzenesulphonyl) indolizine

Into 114 ml of 1,2-dichloroethane were dissolved 13.4 g (0.058 mol) of1-carboethoxy-2-isopropylindolizine and 12.7 g (0.061 mol) of4-methoxybenzenesulphonyl chloride. The solution was stirred and cooledto 0° C. while 23 g (0.174 mol) of aluminum chloride were added by smallfractions.

The addition was terminated after 30 min and the medium was allowed toreturn to room-temperature for 4 hours. After that, the mixture waspoured onto ice and 20 ml of concentrated hydrochloric acid were added.The medium was stirred for 30 min and the organic layer was decanted andwashed with 3 fractions of water. The extract was dried on sodiumsulphate and isolated under vacuum to obtain 24.8 g of a black oil(theory: 22.28 g). This oil was purified on a silica column using firstn-hexane/10%-ethyl acetate and then n-hexane/20%-ethyl acetate aseluents.

In this manner 3.25 g of 1-ethoxycarbonyl2-isopropyl-3-(4-methoxybenzenesulphonyl) indolizine were obtained in aform of a white solid.

Yield: 13.95%.

M.P. 103°-104° C. (hexane/methylene chloride).

b) 1-Carboxy-2-isopropyl-3-(4-hydroxybenzenesulphonyl) indolizine

Into 100 ml of methylene chloride and 25 ml of ethanethiol, weresuspended 6.7 g (0.050 mol) of aluminum chloride. The suspension wasstirred and cooled to 0° C. while 2.5 g of1-ethoxycarbonyl-2-isopropyl-3-(4-methoxybenzenesulphonyl) indolizine inmethylene chloride were added. The addition took about 15 min. Thereaction medium was allowed to return to room-temperature andmaintained, at this temperature, for 45 min. After pouring onto ice, 5ml of concentrated hydrochloric acid were added while stirring and themedium was extracted with 2 fractions of ethyl ether. The etherealextracts were collected and washed with 3 fractions of 30 ml of a10%-aqueous solution of sodium carbonate. The aqueous phase wasacidified and a precipitate was observed.

In this manner 1 g of crude 1-carboxy-2isopropyl-3-(4-hydroxybenzenesulphonyl) indolizine was obtained in theform of a beige solid.

Yield: 44.6%

c) 2-Isopropyl-3-(4-hydroxybenzenesulphonyl) indolizine

For 2 min, 1 g (2.78×10⁻³ mol) of1-carboxy-2-isopropyl-3-(4-hydroxybenzenesulphonyl) indolizine washeated at 200° C. The black residue so obtained was taken up inmethylene chloride and a slight precipitate was eliminated byfiltration. The filtrate was evaporated to provide 0.8 g of a brown oil(theory: 0.877 g). This oil was purified on a silica column using amethylene chloride/ethyl acetate 95/5 mixture as eluent and 0.6 g of agreen oil was isolated. In this manner2-isopropyl-3-(4-hydroxybenzenesulphonyl) indolizine was obtained.

Yield: 68.4%.

Purity: 97.5%.

d)2-Isopropyl-3-[4-{3-[N-methyl-N-(3,4-dimethyoxy-β-phenethyl)amino]propyloxy}benzenesulphonyl]indolizine oxalate

At room-temperature, 0.510 g (1.57×10⁻³ mol) of2-isopropyl-3-(4-hydroxybenzenesulphonyl) indolizine, 0.5 g of potassiumcarbonate and 5 ml of dimethylsulphoxide were stirred for 30 min. Tothis mixture 0.524 g (1.45×10⁻³ mol) of1-chloro-3-[N-methyl-N-(3,4-dimethyoxy-β-phenethyl)amino] propane acidoxalate was added. The stirring was maintained for 16 h atroom-temperature then for 2 h at 50° C. The dimethylsulphoxide waseliminated under vacuum and the residue was taken up in water. Themedium was then twice extracted with ethyl acetate. After that theextracts were twice washed with water and dried on sodium sulphate.After filtration, the filtrate was evaporated under vacuum to obtain0.845 g of an amber-coloured oil. This oil was purified on a silicacolumn using as eluents, ethyl acetate containing 5%, then 10%, then20%-methanol to provide 0.583 g of desired product in free base form(yield: 73%; purity: 99.4%).

The oxalate was formed using 0.530 g of base so obtained and an etherealsolution of oxalic acid. The oxalate was recrystallized from ethylacetate/methanol/ethyl ether.

In this manner 0.473 g of2-isopropyl-3-[4-{3-[N-methyl-N-(3,4-dimethoxy-β-phenethyl)amino]propyloxy}benzenesulphonyl]indolizine oxalate was obtained in the form of a white solid.

M.P.: 135°-137° C.

EXAMPLE 2 Preparation of4-{4-[3-(di-n-butylamino)propyloxy]phenylthio}pyridine dioxalate (SR33683 A)

a) 4-(4-Hydroxy-phenylthio)pyridine

A mixture of 0.0386 mol of 4-(4-methoxy-phenylthio)pyridinehydrochloride in 100 ml of 47%-hydrobromic acid was heated to boilingfor 6 hours. The hydrobromic acid in excess was then distilled off usinga rotary evaporator and the residue was taken up in water. The solutionwas twice washed with ethyl ether and neutralized with a sodiumhydroxide aqueous solution. The precipitate which formed was filteredout, washed with water and dried under vacuum at the temperature of 60°C.

In this manner 4-(4-hydroxy-phenylthio) pyridine was obtained in a yieldof 96%.

M.P.: 240° C. (heptane/isopropanol 6/4).

b) 4-{4-[3-(Di-n-butylamino)propyloxy]phenylthio}pyridine dioxalate

A solution of 0.014 mol of 4-(4-hydroxy-phenylthio)pyridine and 3 g offinely crushed anhydrous potassium carbonate in 50 ml ofdimethylsulphoxide was placed under stirring for 30 min. To this medium0.016 mol of 1-chloro-3-(di-n-butylamino) propane was added and thestirring was maintained at room-temperature for 24 hours. The reactionmedium was poured into water and extracted with ethyl ether. The organicphase was washed with water, dried on sodium sulphate and filtered.After the solvent was evaporated off, an oil was provided which waspurified by chromatography on a silica column (eluent: methanol). Therequired compound in free base form so obtained was then transformedinto an oxalate by adding an ethereal solution of oxalic acid.

In this manner 4-{4-[3-(di-n-butylamino)propyloxy]phenylthio}pyridinedioxalate was obtained in a yield of 80%.

M.P.: 153° C. (ethanol).

Using the same procedures as that described above,4-[4-{3-[N-methyl-N-(3,4-dimethoxy-β-phenethyl)amino]propyloxy}phenylthio]pyridineoxalate (SR 33682A) (Example 3) was obtained.

M.P.: 150° C. (ethanol).

EXAMPLE 4 Preparation of2-{4-[3-di-n-butylamino)propyloxybenzenesulphonyl}pyridine oxalate (SR33692 A)

a) 2-(4-Methoxy-benzenesulphonyl)pyridine

Into 200 ml of dichloromethane was dissolved 0.052 mol of2-[(4-methoxyphenyl)thio]pyridine hydrochloride. To this solution,previously cooled to 0° C., a solution of 0.156 mol of3-chloro-perbenzoic acid in 200 ml of dichloromethane was addeddrop-by-drop and under stirring. The reaction medium was stillmaintained under stirring for 15 min at 0° C. and then the temperaturewas brought to 25° C. The mixture was washed with an aqueous solution ofsodium carbonate then with water. The organic phase was dried onanhydrous sodium sulphate, filtered and distilled using a rotatoryevaporator. The residue so obtained was purified by chromatography on asilica column using a 1,2-dichloro-ethane/ethyl acetate 95/5 mixture aseluent.

In this manner 2-(4-methoxy-benzenesulphonyl)pyridine was obtained in ayield of 78%.

M.P.: 112° C. (isopropanol).

Using the same procedure as that described above4-(4-methoxybenzenesulphonyl)pyridine was prepared.

M.P.: 104° C. (heptane).

b) 2-(4-Hydroxy-benzenesulphonyl)pyridine

A mixture of 0.028 mol of 2-(4-methoxy-benzenesulphonyl)pyridine in 70ml of 47%-hydrobromic acid was heated to reflux for 6 hours. After thisperiod of time, the hydrobromic acid in excess was distilled off. Theresidue so obtained was taken up in water, washed with ethyl ether,treated with active charcoal and filtered. The aqueous solution was thenneutralized with a sodium hydroxide solution and the precipitate whichformed, was filtered out and washed with water. The desired product wasdried under vacuum at 60° C. and recrystallized from aheptane/isopropanol 8/2 mixture.

In this manner 2-(4-hydroxy-benzenesulphonyl)pyridine was obtained in ayield of 88%.

M.P.: 148° C.

Using the same method as that described above,4-(4-hydroxybenzenesulphonyl)pyridine was prepared.

M.P.: 215° C. (heptane/isopropanol 7/3).

c) 2-{4-[3-(di-n-butylamino)propyloxy]benzenesulphonyl}pyridine oxalate

To a solution of 0.0085 mol of 2-(4-hydroxy-benzenesulphonyl)pyridine in50 ml of dimethylsulphoxide, were added 3 g of finely crushed anhydrouspotassium carbonate. The mixture was then maintained under stirring for30 min and 0.015 mol of 1-chloro-3-(di-n-butylamino)propane was added.Stirring was still maintained for 24 hours and the reaction mixture wasthen poured into water and extracted with ethyl ether. The organic layerwas washed with water, dried on sodium sulphate and filtered. After thefiltrate was evaporated, the desired product so obtained was purified bychromatography on a silica column using methanol as eluent. The purebase so obtained was then transformed into an oxalate by addition ofoxalic acid in ethyl ether.

In this manner2-{4-[3-(di-n-butylamino)propyloxy]benzenesulphonyl}pyridine oxalate wasobtained in a yield of 50%.

M.P.: 70° C. (ethyl acetate).

Using the same method as described above, the following compounds wereprepared:

2-[4-{3-[N-methyl-N-(3,4-dimethoxy-β-phenethyl)amino]propyloxy}benzenesulphonyl]pyridineoxalate (SR33691 A) (Example 5)

M.P.: 161.9° C. (ethanol)

4-{4-[3-(di-n-butylamino)propyloxy]benzenesulphonyl}pyridine dioxalate(SR 33685 A) (Example 6)

M.P.: 122° C. (ethyl acetate/ethanol 1/1)

4-[4-{3-[N-methyl-N-(3,4-dimethoxy-β-phenethyl)amino]propyloxy}benzenesulphonyl]pyridineoxalate (SR 33680 A) (Example 7)

M.P.: 160° C. (ethanol)

EXAMPLE 8 Preparation of2-{4-[3-(tertiobutylamino)propyloxy]benzenesulphonyl}pyridine oxalate(SR 33693 A)

To a solution of 0.0042 mol of 2-(4-hydroxy-benzenesulphonyl)pyridine in25 ml of dimethylsulphoxide, was added 1.5 g of finely crushed anhydrouspotassium carbonate. The mixture was stirred for 30 min and 0.0075 molof 1-chloro-3-(N-BOC-tertiobutylamino)propane was added. Stirring wasmaintained for 24 hours and the reaction mixture was then poured intowater. After extraction with ethyl ether the organic phase was washedwith water, dried on sodium sulphate, filtered and evaporated todryness. The oily residue so obtained was stirred at room temperature of185° C. for 20 min and the reaction medium was taken up in water. Themixture was made alkaline with an aqueous solution of sodium hydroxideand extracted with ethyl ether. The ethereal solution was washed withwater, dried on sodium sulphate and filtered. After the solvent waseliminated, a crude product was obtained which was purified bychromatography on a silica column using methanol as eluent. The base sopurified was then transformed into an oxalate by adding an etherealsolution of oxalic acid.

In this manner 2-{4-[3-(tertiobutylamino)propyloxy]benzenesulphonyl}pyridine oxalate was obtained in a yield of 23%.

M.P.: 147° C.

EXAMPLE 9 Preparation of4-{3-[N-methyl-N-(3,4-dimethoxy-β-phenethyl)amino]propyloxy}benzenesulphonylbenzenehydrochloride (SR 33652 A)

a) (4-Hydroxybenzenesulphonyl)benzene

To a solution of 0.05 mol of (4-methoxybenzenesulphonyl)benzene in 150ml of anhydrous benzene, was added 0.02 mol of aluminum chloride and thereaction medium was maintained for about 15 hours under stirring atroom-temperature. After this period of time, the mixture was poured ontocrushed ice. The organic phase was collected, dried on sodium sulphateand evaporated to dryness.

In this manner (4-hydroxybenzenesulphonyl) benzene was obtained in ayield of 68%.

M.P.: 135° C.

b)4-{3-[N-Methyl-N-(3,4-dimethoxy-β-phenethyl)amino]propyloxy}benzenesulphonylbenzenehydrochloride

To a solution of 0.0147 mol of (4-hydroxybenzenesulphonyl) benzene in 25ml of dimethylsulphoxide, was added 0.0294 mol of potassium carbonateand 0.0147 mol of1-chloro-3-[N-methyl-N-(3,4-dimethoxy-β-phenethyl)amino] propane. Themixture was maintained under stirring for 24 hours at room-temperatureand 60 ml of water were added. After extraction with ethyl ether, theorganic phase was dried and evaporated to dryness to obtain an oilproduct. The hydrochloride was formed by adding hydrogen chloride inethyl ether to an ethereal solution of the base so provided.

In this manner,4-{3-[N-methyl-N-(3,4-dimethoxy-β-phenethyl)amino]propyloxy}benzenesulphonylbenzene hydrochloride was obtained in a yield of 30%.

M.P.: 114° C. (ethanol).

Using the same procedure as that described above,4-[3-(di-n-butyl-amino)propyloxy]benzenesulphonylbenzene oxalate wasobtained (SR 31810 A). (Example 10)

Yield: 48%.

M.P.: 78°-81° C. (isopropanol).

EXAMPLE 11 Preparation of2-n-butyl-1-{4-[3-(di-n-butylamino)propyloxy]benzenesulphonyl}benzimidazole acid oxalate (SR 33631A)

a) 2-n-Butyl-1-(4-bromopropoxy-benzenesulphonyl)benzimidazole

A solution of 0.0035 mol of 4-bromopropoxy-benzimidazole, 0.0035 mol of2-n-butyl-benzimidazole and 0.0035 mol of triethylamine in 15 ml ofdioxan was maintained for 7-8 hours under stirring and atroom-temperature. The solvent was eliminated under vacuum to obtain aresidue which was purified by chromatography on a silica column (eluent:dichloromethane/ethyl acetate 9/1).

In this manner 2-n-butyl-1-(4-bromopropoxy-benzenesulphonyl)benzimidazole was obtained and was used as such.

Yield 50%.

b) 2-n-Butyl-1-{4-[3-(di-n-butylamino)propyloxy]benzenesulphonyl}benzimidazole acid oxalate

To a solution of 0.0017 mol of2-n-butyl-1-(4-bromopropoxy-benzenesulphonyl) benzimidazole in 15 ml ofdimethylsulphoxide was added 0.0034 mol of n-butylamine. The reactionmedium was allowed to stand for 17 hours at room-temperature and thenpoured into 50 ml of water. After extraction, the ethereal phase wasdried and evaporated to dryness. The residue so obtained was purified bychromatography on a silica column (eluent: dichloromethane/ethylacetate) to obtain an oil which was the desired product in the form ofthe free base (yield: 50%). The oxalate of the base so provided wasformed by dissolving the base in question into ethyl ether and adding anethereal solution of oxalic acid.

In this manner2-n-butyl-1-{4-[3-(di-n-butylamino)propyloxy]benzenesulphonyl}benzimidazole acid oxalate was obtained after recrystallization fromethanol.

EXAMPLE 12 Preparation of2-isopropyl-3-[4-{3-[N-methyl-N-(3,4-dimethoxy-β-phenethylamino]propyloxy}benzenesulphonyl benzofuran oxalate (SR 33670 A)

A mixture of 0.0021 mol of 2-isopropyl-3-(4-hydroxybenzenesulphonyl)benzofuran, 0.002 mol of1-chloro-3-[N-methyl-N-(3,4-dimethoxy-β-phenethyl)amino] propane and0.0002 mol of potassium carbonate in 2 ml of N,N-dimethylformamide wasstirred at 100° C. for 1 hour. The medium was then poured into water anddistilled in the presence of ethyl acetate. After that the mixture wasdried on sodium sulphate, filtered and concentrated. The residue wastaken up in ethyl acetate and the solution was purified bychromatography on a silica column using methanol as eluent. The oilyproduct so obtained in free base form was taken up in ethyl acetate andone equivalent of oxalic acid in ethyl ether was added. The precipitateso formed was filtered out and recrystallized.

In this manner2-isopropyl-3-[4-{3-[N-methyl-N-(3,4-dimethoxy-β-phenethyl)amino]propyloxy} benzenesulphonyl] benzofuran oxalate was obtained in a yieldof 90%.

M.P.: 151°-158° C. (methanol/ethyl acetate).

Using the same method as that described above, the following compoundswere prepared:

Compounds:

2-n-Propyl-3-[4-{3-[N-methyl-N-(3,4-dimethoxy-β-phenethyl)amino]propyloxy}benzenesulphonyl]benzofuran oxalate (SR 33689 A) (Example 13).

M.P.: 143°-144° C. (methanol/ethyl acetate)

2-n-Propyl-3-[4-{3-[N-methyl-N-(3,4-dimethoxy-β-phenethyl)amino]propyloxy}benzenesulphonyl]benzothiophene hemioxalate (SR 33688A) (Example 14

M.P.: 148°-149° C. (methanol/ethyl acetate).

EXAMPLE 15 Preparation of2-n-butyl-3-[4-{3-[N-methyl-N-(3,4-dimethoxy-β-phenethyl)amino]propyloxy}benzenesulphonyl]benzofuranhydrochloride (SR 33646 A)

a) 2-n-Butyl-3-[4-(3-bromopropyloxy) benzenesulphonyl] benzofuran

To a solution of 0.02 mol of2-n-butyl-3-(4-hydroxy-benzenesulphonyl)benzofuran in 150 ml ofdimethylsulphoxide, was added 0.06 mol of finely crushed anhydrouspotassium carbonate. The mixture was stirred for 1 hour. After that 0.1mol of 1,3-dibromo-propane was added and the reaction medium was heatedto 50° C. for 6 hours. After the reaction was terminated, the mixturewas filtered and evaporated to dryness under vacuum. The residue soobtained was then taken up in dichloroethane, washed with water, thenwith a dilute solution of sodium hydroxide and finally with water. Theorganic phase was evaporated to dryness under vacuum to obtain aresidual oil which was purified by chromatography on a silica column(eluent: hexane/ethyl acetate 9/1).

In this manner,2-n-butyl-3-[4-(3-bromopropyloxy)benzenesulphonyl]benzofuran wasobtained in a yield of 43%.

b)2-n-Butyl-3-[4-{3-[N-methyl-N-(3,4-dimethoxy-β-phenethyl)amino]propyloxy}benzenesulphonyl]benzofuran hydrochloride

A mixture of 0.0086 mol of2-n-butyl-3-[4-(3-bromopropyloxy)benzenesulphonyl] benzofuran, 4 g ofanhydrous potassium carbonate and 0.015 mol ofN-methyl-3,4-dimethoxy-β-phenethylamine in 50 ml of dimethylsulphoxidewas maintained under stirring for 24 hours. The reaction medium waspoured into water and extracted with ethyl ether. The organic solutionwas washed with water, dried on sodium sulphate, filtered and evaporatedto dryness under vacuum. The oily residue was purified by chromatographyon a silica column using, as eluent, a dichlorethane/methanol 9/1mixture. The hydrochloride of the base so provided was formed by addingan ethereal solution of hydrogen chloride.

In this manner,2-n-butyl-3-[4-{3-[N-methyl-N-(3,4-dimethoxy-β-phenethyl)amino]propyloxy}benzenesulphonyl]benzofuranhydrochloride was obtained in a yield of 38%.

M.P.: 60° C. (diisopropyl ether).

EXAMPLE 16 Preparation of2-isopropyl-3-{4-[3-(di-n-butylamino)propyloxy]benzenesulphonyl}pyrazolo[1,5-a]pyridineoxalate (SR 33684A)

a) 2-Isopropyl-3-(4-methoxybenzenesulphonyl)pyrazolo[1,5-a]pyridine

A solution of 0.03 mol of 2-isopropyl-pyrazolo[1,5-a]pyridine and 0.03mol of 4-methoxybenzenesulphonyl chloride in 60 ml of dichloroethane wascooled to -24° C. After that 0.068 mol of aluminum chloride was added inone fraction and the reaction medium was allowed to return toroom-temperature for 3 hours. The mixture was then poured into ice waterand distilled in the presence of ethyl acetate. After drying on sodiumsulphate, the medium was filtered and concentrated. The solid soobtained was then recrystallied from an ethyl acetate/hexane mixture toprovide a product in the form of a white crystalline solid.

In this manner, 0.018 mol of2-isopropyl-3-(4-methoxybenzenesulphonyl)pyrazolo[1,5-a]pyridine wasobtained.

Yield: 60%.

M.P.: 138°-139° C.

b) 2-Isopropyl-3-(4-hydroxybenzenesulphonyl)pyrazolo[1,5-a]pyridine

A mixture of 0.012 mol of2-isopropyl-3-(4-methoxybenzenesulphonyl)pyrazolo[1,5-a]pyridine and0.054 mol of pyridine hydrochloride was heated at 220° C. for 1 hour.Water was then added and the mixture was distilled in the presence ofethyl acetate. The medium was dried on sodium sulphate, filtered andconcentrated. The solid so obtained was then recrystallized fromisopropyl ether to provide a white crystalline product.

In this manner, 0.012 mol of2-isopropyl-3-(4-hydroxybenzenesulphonyl)pyrazolo[1,5-a]pyridine wasobtained.

Yield: 99%.

M.P.: 146.2° C.

c)2-Isopropyl-3-{4-[3-(di-n-butylamino)propyloxy]benzenesulphonyl}pyrazolo[1,5-a]pyridineoxalate

A mixture of 0.003 mol of2-isopropyl-3-(4-hydroxybenzenesulphonyl)pyrazolo[1,5-a]pyridine, 0.003mol of 1-chloro-3-(di-n-butylamino)propane and 0.004 mol of potassiumcarbonate in 6 ml of N,N-dimethylformamide was stirred for 40 min. at100° C. The reaction medium was then poured into water and distilled inthe presence of ethyl acetate. After drying on sodium sulphate, themixture was filtered and concentrated. The residue was then purified ona silica column using an ethyl acetate/hexane 3/7 mixture as eluent. Thebase so obtained, in oily form, was then treated with an etherealsolution of one equivalent of oxalic acid and the precipitate whichformed was filtered out and recrystallized from an ethylether/isopropanol mixture.

In this manner, 0.0028 mol of2-isopropyl-3-{4-[3-(di-n-butylamino)propyloxy]benzenesulphonyl}pyrazolo[1,5-a]pyridineoxalate was obtained.

Yield: 92%.

M.P.: 72° C.

Using the same procedure as that described above,2-isopropyl-3-[4-{3-[N-methyl-N-(3,4-dimethoxy-β-phenethyl)amino]propyloxy}benzenesulphonyl]pyrazolo(1,5-a]pyridineoxalate was obtained (SR 33679A) (Example 17).

M.P.: 144°-147° C. (isopropanol).

EXAMPLE 18 Preparation of2-isopropyl-3-{4-[3-(tertiobutylamino)propyloxy]benzenesulphonyl}pyrazolo[1,5-a]pyridineoxalate (SR 33686A)

a)2-Isopropyl-3-[4-(3-bromopropyloxy)benzenesulphonyl]pyrazolo[1,5-a]pyridin

A mixture of 0.003 mol of2-isopropyl-2-(4-hydroxybenzenesulphonyl)pyrazolo[1,5-a]pyridine, 0.064mol of 1,3-dibromopropane and 0.004 mol of potassium carbonate in 6 mlof N,N-dimethylformamide was stirred at 100° C. for one hour. The mediumwas then poured into water and distilled in the presence of ethylacetate. After drying on sodium sulfate, the mixture was filtered andconcentrated to obtain a residue which was purified on a silica columnusing an ethyl acetate/hexane 1/1 mixture.

In this manner, 0.0021 mol of2-isopropyl-3-[4-(3-bromopropyloxy)benzenesulphonyl]pyrazolo[1,5-a]pyridinewas obtained in the form of a viscous oil.

Yield: 69%.

b)2-Isopropyl-3-{4-[3-(tertiobutylamino)propyloxy]benzenesulphonyl}pyrazolo[1,5-a]pyridineoxalate

In a flask, a solution of 0.002 mol of2-isopropyl-3-[4-(bromopropyloxy)benzenesulphonyl]pyrazolo[1,5-a]pyridineand 0.008 mol of tertiobutylamine in 4 ml of N,N-dimethylsulphoxide wasstirred at room-temperature for 24 hours. The mixture was poured intowater and then distilled in the presence of ethyl acetate. After dryingon sodium sulphate, the medium was filtered and concentrated to obtain abase in oily form. A solution of this base in an ethyl ether/ethylacetate mixture was then treated with one equivalent of oxalic acid andthe white precipitate so obtained was recrystallized from an ethylether/isopropanol mixture.

In this manner, 0.002 mol of2-isopropyl-3-{4-[3-(tertiobutylamino)propyloxy]benzenesulphonyl}pyrazolo[1,5-a]pyridineoxalate was obtained.

Yield: 99%.

M.P.: 208° C.

EXAMPLE 19 Preparation of2-isopropyl-3-[4-{3-[N-methyl-N-(3,4-dimethoxy-β-phenethyl)amino]propyloxy}benzenesulphonyl]-4,5-dihydro-furanoxalate (SR 33681A)

a) 1-(4-Tosyloxybenzenesulphonyl)-3-methyl-butan-2-one

A mixture of 0.1 mol of sodium 4-tosyloxysulphinate and 0.1 mol ofbromomethyl isopropyl ketone in 400 ml of N,N-dimethylformamide wasstirred at 85° C. for 90 min. The mixture was then poured onto ice andfiltered on fritted glass. The pasty residue so obtained wassuccessively washed twice with water, once with 200 ml of ethanol andfinally with ethyl ether. After drying under vacuum for 2 hours thedesired product was provided after recrystallization from ethyl acetate.

In this manner, 0.074 mol of1-(4-tosyloxybenzenesulphonyl)-3-methylbutan-2-one was obtained in theform of a white solid.

Yield: 74%.

M.P.: 160° C.

b) 1-Isobutyryl-1-(4-tosyloxybenzenesulphonyl)cyclopropane

A mixture of 0.05 mol of1-(4-tosyloxybenzenesulphonyl)-3-methyl-butan-2-one, (0.05 mol) of1,2-dibromo-ethane and 0.12 mol of potassium carbonate in 100 ml ofN,N-dimethylformamide was stirred at room-temperature for 60 hours. Thereaction mixture was poured into water, acidified with dilutehydrochloric acid and extracted with ethyl acetate. After drying onsodium sulphate, the medium was filtered and concentrated. The residueso obtained was then purified by chromatography on a silica column usingan ethyl acetate/hexane 3/7 mixture as eluent.

In this manner, 0.026 mol of1-isobutyryl-1-(4-tosyloxybenzenesulphonyl)cyclopropane was obtained ina yield of 53%.

M.P.: 106°-107° C.

c) 1-isobutyryl-1-(4-hydroxybenezenesulphonyl)cyclopropane

Into 85 ml of ethanol heated to 80° C., was dissolved 0.026 mol of1-isobutyryl-1-(4-tosyloxybenzenesulphonyl)cyclopropane. A solution of0.05 mol of sodium hydroxide in 30 ml of water was then added and themedium was maintained at 80° C. for 10 min. The ethanol was eliminatedunder reduced pressure and the residue was taken up in dilutehydrochloric acid and distilled in the presence of ethyl acetate. Afterdrying on sodium sulphate, the medium was filtered and concentrated. Theresidue so obtained was then purified by chromatography on a silicacolumn using an ethyl acetate/hexane 1/1 mixture.

In this manner, 0.016 mol of1-isobutyryl-1-(4-hydroxybenzenesulphonyl)cyclopropane was obtained inthe form of a white solid.

Yield: 60%.

M.P.: 111°-112° C. (ethyl acetate).

d)1-isobutyryl-1-[4-{3-[N-methyl-N-(3,4-dimethoxy-β-phenethyl)amino]propyloxy}benzenesulphonyl]cyclopropane

A mixture of 0.005 mol of1-isobutyryl-1-(4-hydroxybenzenesulphonyl)cyclopropane, 0.0048 mol of1-chloro-3-[N-methyl-N-(3,4-dimethoxy-β-phenethyl)amino]propane and0.005 mol of potassium carbonate in 5 ml of N,N-dimethylformamide washeated at 140° C. for 15 min. The reaction mixture was then poured intowater and distilled in the presence of ethyl acetate. After drying onsodium sulphate, the medium was filtered and concentrated. The residuewas then purified by chromatography on a silica column using an ethylacetate/hexane 1/1 mixture.

In this manner, 0.0033 mol of1-isobutyryl-1-[4-{3-[N-methyl-N-(3,4-dimethoxy-β-phenethyl)amino]propyloxy}benzenesulphonyl]cyclopropanewas obtained in oily form.

Yield: 66%.

e)2-Isopropyl-3-[4-{3-[N-methyl-N-(3,4-dimethoxy-β-phenethyl)amino]propyloxy}benzenesulphonyl]-4,5-dihydro-furanoxalate

A mixture of 0.002 mol of1-isobutyryl-1-[4-{3-[N-methyl-N-(3,4-dimethoxy-β-phenethyl)amino]propyloxy}benzenesulphonyl]cyclopropaneand 0.003 mol of tricaprylylmethyl ammonium chloride was heated at 115°C. for 30 min. The reaction medium was then purified by chromatographyon a silica column using an ethyl acetate/hexane 1/1 mixture to obtain abase in oily form. An ethereal solution of the base so provided was thentreated with one equivalent of oxalic acid in ethyl ether.

In this manner, 0.0013 mol of2-isopropyl-3-[4-{3-[N-methyl-N-(3,4-dimethoxy-β-phenethyl)amino]propyloxy}benzenesulphonyl]-4,5-dihydro-furanoxalate was obtained in the form of a white solid.

Yield: 65%.

M.P.: 147.2° C. (methanol).

EXAMPLE 20 Preparation of2-isopropyl-3-{4-[3-(di-n-butylamino)propyloxy]benzenesulphonyl}quinolineoxalate (SR 33695 A)

a) 2-Isopropyl-3-(4-tosyloxybenzenesulphonyl)quinoline

In a sealed tube a mixture of 0.02 mol of 2-aminobenzaldehyde and 0.02mol of 1-(4-tosyloxybenzenesulphonyl)-3-methyl-butan-2-one was heated at185° C. for 2 hours. The mixture was then taken up in dry ethyl etherand filtered.

M.P. of the hydrochloride: about 90° C.

b) 2-Isopropyl-3-(4-hydroxybenzenesulphonyl)quinoline

To a solution of 0.017 mol of2-isopropyl-3-(4-tosyloxybenzenesulphonyl)quinoline in 250 ml ofethanol, was added a solution of 0.068 mol of sodium hydroxide in 5 mlof water. The mixture was heated to reflux for 2 hours and then thesolvent was eliminated. The residue so obtained was taken up in waterand neutralized with acetic acid. The precipitate which formed was thenfiltered out, dried and recrystallized from a dichloroethane/heptane 1/1mixture.

In this manner, 2-isopropyl-3-(4-hydroxybenzenesulphonyl) quinoline wasobtained in a yield of 58%.

M.P.: 185° C.

c)2-Isopropyl-3-{4-[3-(di-n-butylamino)propyloxy]benzenesulphonyl}quinolineoxalate

To a solution of 0.005 mol of2-isopropyl-3-(4-hydroxybenzenesulphonyl)quinoline in 25 ml ofdimethylsulphoxide, was added 0.015 mol of anhydrous potassiumcarbonate. The mixture was stirred for 30 min. and 0.0075 mol of1-chloro-3-(di-n-butylamino)propane was added. The reaction medium wasmaintained under stirring for 24 hours. After this period of time, themixture was poured into water and extracted with ethyl ether. Theorganic phase was washed with water, dried on sodium sulphate, filteredand evaporated to dryness. An oily base was so provided which waspurified by chromatography on a silica column (eluent: isopropanol) andtransformed into an oxalate by adding oxalic acid in ethyl ether.

In this manner2-isopropyl-3-{4-[3-(di-n-butylamino)-propyloxy]benzenesulphonyl}quinolineoxalate was obtained in a yield of 55%.

M.P.: 130° C. (ethanol).

Using the same method as that described above,2-isopropyl-3-[4-{3-[N-methyl-N-(3,4-dimethoxy-β-phenethyl)amino]propyloxy}benzenesulphonyl]quinolineoxalate (SR 33694 A) (Example 21).

M.P.: 162° C. (ethanol).

EXAMPLE 22 Preparation of5-[4-{3-[N-methyl-N-(3,4-dimethoxy-β-phenethyl)amino]propyloxy}benzenesulphonyl]-6-isopropyl-pyrrolo[1,2-b]pyridazineoxalate (SR 33687A)

a) 3-(4-Tosyloxybenzenesulphonyl)methyl-pyridazine

To a solution of 0.13 mol of 3-chloromethyl-pyridazine hydrochloride in400 ml of dimethylsulphoxide was added 0.13 mol of sodium bicarbonate.The mixture was stirred for 30 min. and 0.195 mol of sodium4-tosyloxybenzenesulphonate was introduced. The reaction medium wasmaintained under stirring for 2 hours at room-temperature then for 2hours at 50° C. The mixture was poured into 3 l of water and theprecipitate so formed was filtered, washed with water and dried undervacuum.

In this manner, 3-(4-tosyloxybenzenesulphonyl)methyl-pyridazine wasobtained in a yield of 82%.

M.P.: 161° C. (ethanol).

b) 5-(4-Tosyloxybenzenesulphonyl)-6-isopropyl-pyrrolo[1,2-b]pyridazine.

A mixture of 0.011 mol of 3-(4-tosyloxybenzenesulphonyl)methylpyridazineand 0.011 mol of 1,8-diazabicyclo[5,4,0]undec-7ene in 40 ml ofhexamethylphosphoramide was heated at 75° C. for 30 min. After that 4 gof bromomethyl isopropyl ketone were added while maintaining the sametemperature for 6 hours. The mixture was poured into 200 ml of water andextracted with dichloroethane. The organic solution was washed withwater, dried on sodium sulphate and filtered. The solvent was eliminatedunder vacuum to provide an oily residue which was purified bychromatography on a silica column (eluent: dichloroethane).

In this manner,5-(4-tosyloxybenzenesulphonyl)-6-isopropyl-pyrrolo[1,2-b]pyridazine wasobtained in crystalline form.

Yield: 7%

M.P.: 149° C. (isopropanol).

c) 5-(4-Hydroxybenzenesulphonyl)-6-isopropyl-pyrrolo[1,2-b]pyridazine.

A solution of 0.0034 mol of5-(4-tosyloxybenzenesulphonyl)-6-isopropylpyrrolo[1,2-b]pyridazine in 75ml of ethanol was heated to boiling and a solution of 0.0034 mol ofsodium hydroxide in 3 ml of water was added. Boiling was maintained for6 hours. The solvent was eliminated and the residue was taken up inwater and neutralized with acetic acid. The precipitate so formed wastaken up in dichloroethane and the solution was washed with water, driedon sodium sulphate and filtered. The solvent was finally evaporated off.

In this manner,5-(4-hydroxybenzenesulphonyl)-6-isopropyl-pyrrolo[1,2-b]pyridazine wasisolated in a yield of 75%.

d)5-[4-{3-[N-Methyl-N-(3,4-dimethoxy-β-phenethyl)amino]propyloxy}benzenesulphonyl]-6-isopropyl-pyrrolo[1,2-b]pyridazineoxalate

A mixture of 0.0022 mol of5-(4-hydroxybenzenesulphonyl)-6-isopropylpyrrolo[1,2-b]pyridazine and1.5 g of anhydrous potassium carbonate in 25 ml of dimethylsulphoxidewas stirred for 30 min. After that, 0.0027 mol of1-chloro-3-[N-methyl-N-(3,4-dimethoxy-β-phenethyl)amino]propane oxalatewas added and stirring was maintained at room-temperature for 18 hours.The reaction medium was then heated at 50° C. for 5 hours, poured intowater, and extracted with ethyl ether. The ethereal phase was washedwith water, dried on sodium sulphate and filtered. After evaporating thesolvent, an oily residue was obtained which was purified bychromatography and a silica column using methanol as eluent. The oxalatewas formed by adding oxalic acid in ethanol ether to an etherealsolution of the base as provided.

In this manner,5-[4-{3-[N-methyl-N-(3,4-dimethoxy-β-phenethyl)amino]propyloxy}benzenesulphonyl]-6-isopropyl-pyrrolo[1,2-b]pyridazineoxalate was obtained in a yield of 57%.

M.P: 88° C. (ethyl acetate/isopropanol).

EXAMPLE 23 Preparation of2-isopropyl-3-[4-{3[N-methyl-N-(3,4-dimethoxy-β-phenethyl)amino]propyloxy}benzenesulphonyl]furanoxalate (SR 33697 A)

a) 2-Isopropyl-3-(4-tosyloxybenzenesulphonyl-4,5-dihydro-furan

A mixture of 0.008 mol of1-isobutyryl-1-(4-tosyloxybenzenesulphonyl)cyclopropane and 0.022 mol oftricaprylylmethyl ammonium chloride was heated at 130° C. for 30 min.The reaction mixture was then chromatographed on a silica column usingan ethyl acetate/hexane 25/75 mixture as eluent.

In this manner, 0.0145 mol of2-isopropyl-3-(4-tosyloxybenzenesulphonyl)-4,5-dihydro-furan wasobtained in the form of a white solid.

Yield: 66%.

M.P.: 103° C. (ethyl acetate/hexane).

b) 2-Isopropyl-3-(4-tosyloxybenzenesulphonyl) furan

A mixture of 0.035 mol of2-isopropyl-3-(4-tosyloxybenzenesulphonyl)-4,5-dihydro-furan, 1 mol ofmanganese dioxide and 3 Å-molecular screen in powder (previously driedat 140° C. under 0.01 mm Hg for 5 h) in 400 ml of dry ethyl ether wasstirred for 66 hours at room-temperature. The mixture was then filteredand the solid was rinsed with dichloromethane. After concentration themedium was chromatographed on a silica column using an ethylacetate/hexane 2/8 mixture.

In this manner, 0.009 mol of 2-isopropyl-3-(4-tosyloxybenzenesulphonyl)furan was obtained in a yield of 25%.

M.P.: 94° C. (ethyl acetate/hexane).

c) 2-Isopropyl-3-(4-hydroxybenzenesulphonyl)furan

To a solution of 0.008 mol of 2-isopropyl-3-(4-tosyloxybenzenesulphonyl)furan in 1.8 ml of ethanol were added 18 ml of1N-sodium hydroxide. The milky solution was stirred under reflux tocomplete dissolution (2 minutes) and the reaction medium was cooled andneutralized with dilute hydrochloric acid. After that, the mixture wasdistilled in the presence of ethyl acetate. The organic phase was driedon sodium sulphate, filtered and concentrated. The residue so obtainedwas then purified on a silica column and eluted using an ethylacetate/hexane 4/6 mixture.

In this manner, 0.0073 mol of2-isopropyl-3-(4-hydroxybenzenesulphonyl)furan was obtained in a yieldof 91%.

M.P.: 131° C. (ethyl acetate/hexane).

d)2-Isopropyl-3-[4-{3-[N-methyl-N-(3,4-dimethoxy-β-phenethyl)amino]propyloxy}benzenesulphonyl]furanoxalate

A mixture of 0.003 mol of2-isopropyl-3-(4-hydroxybenzenesulphonyl)furan, 0.003 mol of1-chloro-3-[N-methyl-N-(3,4-dimethoxy-β-phenethyl)amino]propane and3.23×10⁻³ mols of crushed potassium carbonate in 3 ml ofN,N-dimethylformamide was heated at 100° C. for 30 minutes. The mixturewas then poured into water and distilled in the presence of ethylacetate. After drying on sodium sulphate, the medium was filtered andconcentrated. The residue so obtained was then purified bychromatography on a silica column using methanol as eluent. After that,the base so provided was transformed into oxalate by adding oxalic acidin ethyl ether.

In this manner, 0.00288 mol of2-isopropyl-3-[4-{3-[N-methyl-N-(3,4-dimethoxy-β-phenethyl)amino]propyloxy}benzenesulphonylfuran oxalate was obtained.

Yield: 96%.

M.P.: 102° C. (chloroform/ethyl acetate).

Using the same method as described above,2-isopropyl-3-}4-[3-(di-n-butylamino)propyloxy]benzenesulphonyl}furanoxalate (SR 33701 A) (Example 24) was obtained in a yield of 92%.

M.P.: 98° C. (ethanol/ethyl ether).

EXAMPLE 25 Preparation of2-isopropyl-3-{4-[3-(tert-butylamino)propyloxy]benzenesulphonyl}furanoxalate (SR 33702 A)

a) 2-Isopropyl-3-[4-(3-bromopropyloxy)benzenesulphonyl]furan

A mixture of 0.003 mol of 2-isopropyl-3-(4-hydroxybenzenesulphonyl)furan, 0.06 mol of 1,3-dibromopropane and 0.005 mol of crushed potassiumcarbonate in 8 ml of N,N-dimethylformamide was heated at 100° C. for 1hour. The mixture was poured into water and distilled in the presence ofethyl acetate. After drying on sodium sulphate, the medium was filteredand concentrated. The residue so obtained was then purified bychromatography on a silica column using an ethyl acetate/hexane 2/8mixture.

In this manner, 0.00282 mol of2-isopropyl-3-[4-(3-bromopropyloxy)benzenesulphonyl]furan was obtainedin oily form.

Yield: 94%.

b) 2-Isopropyl-3-{4-[3-(tert-butylamino)propyloxy]benzenesulphonyl}furanoxalate

A mixture of 0.00282 mol of2-isopropyl-3-[4-(3-bromopropyloxy)benzenesulphonyl]furan and 0.013 molof tert-butylamine in 7 ml of dimethylsulphoxide was stirred atroom-temperature for 24 hours. After that, the mixture was poured intowater, distilled in the presence of ethyl acetate, dried on sodiumsulphate, filtered and concentrated. The residue so obtained waspurified on a silica column using a methanol/ethyl acetate 2/8 mixtureas eluent. The oily base so provided was then treated with an etherealsolution of oxalic acid and the precipitate was recrystallized fromethanol.

In this manner, 0.0023 mol of2-isopropyl-3-{4-[3-(tert-butylamino)propyloxy[benzenesulphonyl}furanoxalate was obtained in a yield of 82%.

M.P.: 143.6° C.

EXAMPLE 26 Preparation of4-[4-{3-[N-methyl-N-(3,4-dimethoxy-β-phenethyl)amino]propyloxy}phenylthio]cinnolineoxalate (SR 33699A)

a) 4-(4-Methoxyphenylthio)cinnoline

To a solution of sodium methylate prepared from 0.7 g (0.03 at g.) ofsodium in 25 ml of methanol, there were added 4.2 g (0.03 mol) of4-methoxyphenylthiol. The methanol in excess was eliminated using arotatory evaporator and the sodium salt so obtained was dried under highvacuum and then dissolved into 100 ml of N,N-dimethylformamide. Afterthat, 4.38 g (0.03 mol) of 4-chlorocinnoline were added. The medium wasstirred at room-temperature for 24 hours and then poured into water.After filtration, the product was washed on the filter with water andthen dried under vacuum at the temperature of 60° C.

In this manner 6.4 g of 4-(4-methoxyphenylthio)cinnoline were obtainedin a yield of 80%.

M.P.: 163° C. (7/3 isopropanol/heptane)

Using the same procedure as that described above but from3-bromocinnoline there was obtained 3-(4-methoxyphenylthio)cinnoline.

Yield: 74.6%

M.P.: 108° C. (isopropanol)

b) 4-(4-Hydroxyphenylthio)cinnoline

To a solution of 3.6 g (0.0134 mol) of 4-(4-methoxyphenylthio)cinnoline,there were added 30 ml of 47%-hydrobromic acid. The mixture was stirredand heated at 125° C. for 4 hours. The hydrobromic acid in excess wasthen eliminated with a rotatory evaporator and the residue obtained wastaken up with water. The solution was neutralized with sodiumbicarbonate and filtered. The product so isolated was washed on thefilter with water and dried under vacuum at the temperature of 60° C.

In this manner, 2.9 g of 4-(4-hydroxyphenylthio)cinnoline were obtainedafter recrystallization from a 7/3 isopropanol/heptane mixture.

Yield: 85%.

M.P.: 238° C.

Using the same procedure described above but from3-(4-methoxyphenylthio)cinnoline, there was obtained3-(4-hydroxyphenylthio)cinnoline in a yield of 90%.

c)4-[4-{3-[N-methyl-N-(3,4-dimethoxy-β-phenethyl)amino]propyloxy}phenylthio]cinnolineoxalate.

A mixture of 2.5 g (0.01 mol) of 4-(4-hydroxyphenylthio)cinnoline and 7g of crushed anhydrous potassium carbonate in 50 ml ofdimethylsulphoxide was stirred for 30 min. After that 4.4 g (0.012 mol)of 1-chloro-3-[N-methyl-N-(3,4-dimethoxy-β-phenethyl)amino]propaneoxalate were added while stirring was maintained for 24 hours atroom-temperature. The medium was poured into water and extracted withethyl ether. The ethereal solution was washed with water, dried onanhydrous sodium sulphate and filtered. The ethyl ether was eliminatedwith a rotatory evaporator to obtain 5.3 g of an oil which was purifiedby chromatography on a silica column using methanol as eluent. The baseso provided (4.7 g) was then transformed into an oxalate in ethyl ethermedium and the salt was recrystallized from ethanol.

In this manner 4.1 g of4-[4-{3-{N-methyl-N-(3,4-dimethoxy-β-phenethyl)amino]propyloxy}phenylthio]cinnolineoxalate were obtained.

Yield: 70.8%

M.P.: 138° and 160° C.

Using the same procedure as that described above but from3-(4-hydroxyphenylthio)cinnoline there was prepared3-[4-{3-[N-methyl-N-(3,4-dimethoxy-β-phenethyl)amino]propyloxy}phenylthio]cinnolineoxalate (Example 27) (SR 33704 A)

Yield: 67.6%

M.P.: 166° C.

EXAMPLE 28 Preparation of3-[4-{3-[N-methyl-N-(3,4-dimethoxy-β-phenethyl)amino]propyloxy}benzenesulphonyl]cinnolineoxalate (SR 33703A)

a) 3-(4-Hydroxybenzenesulphonyl)cinnoline

A mixture of 2.1 g (0.01 mol) of 3-bromocinnoline, 6.6 g (0.02 mol) ofsodium 4-tosyloxybenzenesulphinate and 50 ml of dimethylsulphoxide wasstirred and heated at 120° C. for 24 hours. The mixture was poured intowater and extracted with dichloroethane. The dichlorethane solution waswashed with water, dried on anhydrous sodium sulphate and filtered. Thesolvent was then evaporated with a rotary evaporator to provide 2.5 g ofan oily residue. The desired product was then isolated by chromatographyon a silica column using dichloroethane/methanol 98/2.

In this manner, 0.45 g of 3-(4-hydroxybenzenesulphonyl)cinnoline wasobtained.

Yield; 10.2%

b)3-[4-{3-[N-Methyl-N-(3,4-demethoxy-β-phenethyl)amino]propyloxy}benzenesulphonyl]cinnolineoxalate.

A mixture of 0.2 g (0.0007 mol) of3-(4-hydroxybenzenesulphonyl)cinnoline and 0.4 g of potassium carbonatein 10 ml of dimethylsulphoxide was stirred for 30 min. After that, 0.3 g(0.0008 mol) of1-chloro-3-[N-methyl-N-(3,4-dimethoxy-β-phenethyl)amino]propane oxalatewas added and the stirring was maintained for 24 hours atroom-temperature. The medium was poured into water and extracted withethyl ether. The ethereal solution was washed with water, dried onanhydrous sodium sulphate and filtered. The ethyl ether was theneliminated using a rotatory evaporator and the residue was purified bychromatography on a silica column using methanol as solvent to provide0.100 g (30%) of a base. This base was then transformed into an oxalatein ethyl ether by adding an ethereal solution of oxalic acid and thesalt so formed was recrystallized from ethanol.

In this manner, 0.100 g of3-[4-{3-[N-methyl-N-(3,4-dimethoxy-β-phenethyl)amino]propyloxy}benzenesulphonyl]cinnolineoxalate was obtained.

M.P.: 158° C.

EXAMPLE 29 Preparation of2-isopropyl-1-[4-{3-[N-methyl-N-oxide-N-(3,4-dimethoxy-β-phenethyl)amino]propyloxy}benzenesulphonyl]indolizineacid oxalate.

A solution of 2.75 g (0.005 mol) of2-isopropyl-1-[4-{3-[N-methyl-N-(3,4-dimethoxy-β-phenethyl)amino]propyloxy}benzenesulphonyl]indolizinein 40 ml of dichloromethane was cooled to -10° C. Under stirring, 1 g(0.005 mol) of 3-chloroperbenzoic acid in 40 ml of dichloromethane wasadded to the reaction medium which was then allowed to return toroom-temperature. The mixture was washed with a sodium carbonatesolution and then with water. After drying on sodium sulphate andfiltering, the solvent was evaporated off using a rotatory evaporator.The residue so obtained (3.1 g) was then purified by chromatography on asilica column using methanol as solvent to obtain the required N-oxidederivative in free base form. The oxalate was then formed by adding anethereal solution of oxalic acid to a solution, of the base so provided,in tetrahydrofuran/ethyl ether.

In this manner,2-isopropyl-1-[4-{3-[N-methyl-N-oxide-N-(3,4-dimethoxy-β-phenethyl)amino]propyloxy}benzenesulphonyl]indolizineacid oxalate was obtained. The N.M.R. spectrum was found to be correct.

EXAMPLE 30 Preparation of1-benzyl-2-[4-{3-[N-methyl-N-(3,4-dimethoxy-β-phenethyl)amino]propyloxy}benzenesulphonyl]imidazole(SR 33776)

a) N-Benzylimidazole.

To a solution of 24 g (1 mol) of sodium hydride in 500 ml ofN,N-dimethylformamide, there was added, drop-by-drop, a solution of 68 g(1 mol) of imidazole in 150 ml of N,N-dimethylformamide. The medium wasstirred for 2 hours and then 126.6 g (1 mol) of benzyl chloride wereadded. The solvent was eliminated and the residue was taken up withethyl acetate and washed with water. The organic phase was dried andconcentrated to provide an oil which crystallized when cold.

In this manner, N-benzylimidazole was obtained in a yield of 70%.

b) 1-Benzyl-2-(4-methoxybenzenesulphonyl)imidazole.

To a solution of 44 g (0.28 mol) of 1-benzylimidazole in 200 ml ofacetonitrile, there were added, drop-by-drop, 57.5 g (0.28 mol) of4-methoxybenzenesulphonyl chloride dissolved into 50 ml of acetonitrile.After one hour, 41.5 ml (0.31 mol) of triethylamine were added and themedium was maintained under stirring for 12 hours. The precipitate wasisolated and the solution was purified by high pressure liquidchromatography using dichloromethane as eluent.

In this manner, 1-benzyl-2-(4-methoxybenzenesulphonyl)imidazole wasobtained in a yield of 5%.

c) 1-Benzyl-2-(4-hydroxybenzenesulphonyl)imidazole.

A mixture of 2.6 g (8×10⁻³ mol) of1-benzyl-2-(4-methoxybenzenesulphonyl)imidazole in 10 ml of iodhydricacid was heated for 5 hours at 170° C. The reaction medium was thenpoured into ice water and extracted with ethyl acetate. The organicphase was dried and concentrated and the residue obtained was purifiedby high pressure liquid chromatography using dichloromethane as eluent.

In this manner, 1-benzyl-2-(4-hydroxybenzenesulphonyl)imidazole wasobtained in a yield of 20%.

d)1-Benzyl-2-[4-{3-[N-methyl-N-(3,4-dimethoxy-β-phenethyl)amino]propyloxy}benzenesulphonyl]imidazole.

A mixture of 0.5 g (1.6×10⁻³ mol) of1-benzyl-2-(4-hydroxybenzenesulphonyl)imidazole, 0.86 g (2.4×10⁻³ mol)of 1-chloro-3-[N-methyl-N-(3,4-dimethoxy-β-phenethyl)amino]propaneoxalate and 1.1 g (7.9×10⁻³ mol) of potassium carbonate in 6 ml ofdimethylsulphoxide was maintained at 35° C. for 3 days. The reactionmedium was then poured into ice water and the oil so obtained waspurified by high pressure liquid chromatography using ethyl acetate aseluent.

Yield: 78%.

EXAMPLE 31 Preparation of1-isopropyl-2-[4-{3-[N-methyl-N-(3,4-dimethoxy-β-phenethyl)amino]propyloxy}benzenesulphonyl]benzimidazoleoxalate

a) 1-Isopropyl-2-(4-benzyloxybenzenesulphonyl)benzimidazole. To asolution of 7.08×10⁻⁴ mol of 4-benzyloxybenzenesulphonyl chloride in 10ml of acetonitrile cooled to 0° C., there was added 7.08×10⁻⁴ mol of1-isopropylbenzimidazole prepared in N,N-dimethylformamide frombenzimidazole and isopropyl bromide in the presence of sodium hydride.After that one equivalent of triethylamine was added. The medium wasstirred at room-temperature for 12 hours and the acetonitrile was thenevaporated off. The residue so obtained was then taken up with water andextracted several times with dichloromethane. The organic extracts werecollected, dried and evaporated. The residue so provided was purified bychromatography on a silica column using a dichloromethane/ethyl acetate99/1 mixture as eluent.

In this manner, 1-isopropyl-2-(4-benzyloxybenzenesulphonyl)benzimidazolewas obtained in a yield of 52%.

M.P.: 94°-96° C.

b) 1-Isopropyl-2-(4-hydroxybenzenesulphonyl)benzimidazole.

To 20 ml of ethanol, there were added 2.95×10⁻⁴ mol of1-isopropyl-2-(4-benzyloxybenzenesulphonyl)benzimidazole and 0.015 g of10%-palladium charcoal and the mixture so obtained was maintained underhydrogen atmosphere. When the required quantity of hydrogen was absorbednamely after about 2 hours, the catalyst was filtered out and washedwith ethanol. The alcoholic extracts were collected and evaporated undervacuum.

In this manner 1-isopropyl-2-(4-hydroxybenzenesulphonyl)benzimidazolewas obtained in the form of a white crystalline product.

Yield: 64%

M.P.: 198° C.

c)1-Isopropyl-2-[4-{3-[N-methyl-N-(3,4-dimethoxy-β-phenethyl)amino]propyloxy}benzenesulphonyl]benzimidazoleoxalate.

To a mixture of 1.42×10⁻⁴ mol of1-isopropyl-2-(4-hydroxybenzenesulphonyl)benzimidazole and 5 equivalentsof potassium carbonate in 5 ml of dimethylsulphoxide, there was added1.5 equivalent of1-chloro-3-[N-methyl-N-(3,4-dimethoxy-β-phenethyl)amino]propane oxalate.The medium was stirred for about 15 hours at 35° C. and the residue waspoured on ice and extracted with ethyl acetate. The organic phase wasthen dried and evaporated and the base so provided was purified bychromatography on a silica column using an ethyl acetate/methanol 95/5mixture. The oxalate was then formed using an etheral solution of oxalicacid.

In this manner,1-isopropyl-2-[4-{3-[N-methyl-N-(3,4-dimethoxy-β-phenethyl)amino]propyloxy}benzenesulphonyl]benzimidazoleoxalate was obtained.

EXAMPLE 32 Preparation of2-[4-{3-[N-methyl-N-(3,4-dimethoxy-β-phenethyl)amino]propyloxy}benzenesulphonyl]pyrimidineoxalate

a) 2-(4-Methoxybenzenesulphonykl)pyrimidine.

To 8.7×10⁻² mol of 50%-sodium hydride in 20 ml of N,N-dimethylformamide,there were added 12.3 g (8.7×10⁻² mol) of 4-methoxyphenylthiol. Afterthe gaseous evolution was terminated namely after about 2 hours, 10 g(8.7×10⁻² mol) of 2-chloropyrimidine in 100 ml of N,N-dimethylformamidewere added. The medium was stirred at room-temperature for 3 hours andthe slight precipitate was filtered out. After evaporation of thesolvent, the oily residue was taken up in 100 ml of water and themixture was stirred. The product which crystallized was then filteredout and washed with water.

In this manner, 2-(4-methoxybenzenesulphonyl)pyrimide was obtained in ayield of 89%.

M.P.: 72° C.

b) 2-(4-Hydroxybenzenesulphonyl)pyrimidine.

A mixture of 4.6×10⁻³ mol of 2-(4-methoxybenzenesulphonyl)pyrimidine and10 ml of 47%-hydrobromic acid was heated for 1 hour at 90° C. Thereaction medium was neutralized to a pH of 7 with an ammonia solutionand the pasty residue was extracted with dichloromethane. The organicphase was then dried and evaporated and the residue so provided waspurified by chromatography on a silica column using dichloromethane aseluent.

In this manner, 2-(4-hydroxybenzenesulphonyl)pyrimidine was obtained.

c)2-[4-{3-[N-methyl-N-(3,4-dimethoxy-β-phenethyl)amino]propyloxy}benzenesulphonyl]pyrimidineoxalate.

To a mixture of 1.6×10⁻³ mol of 2-(4-hydroxybenzenesulphonyl)pyrimidine,2.4×10⁻³ mol of1-chloro-3-[N-methyl-N-(3,4-dimethoxy-β-phenethyl)amino]propane oxalateand 1.1 g of potassium carbonate was maintained at 35° C. for severalhours and the residue was poured on ice and extracted with ethylacetate. The organic phase was then dried and evaporated and the base soprovided was purified by chromatography on a silica column. The oxalatewas then formed using an ethereal solution of oxalic acid.

In this manner2-[4-{3-[N-methyl-N-(3,4-dimethoxy-β-phenethyl)amino]propyloxy}benzenesulphonyl]pyrimidineoxalate was obtained.

EXAMPLE 33 Preparation of2-[4-{3-N-methyl-N-(3,4-dimethoxy-β-phenethyl)amino]propyloxy}benzenesulphonyl]indeneoxalate (SR 33705 A)

a) 3-Chloro-2-(4-tosyloxybenzenesulphonyl)indane.

Under nitrogen atmosphere, a mixture of 0.05 mol of indene, 0.05 mol ofsulphonyl chloride, 0.0005 mol of cupric chloride and 0.0005 mol oftriethylamine hydrochloride in 3 ml of acetonitrile was heated at 115°C. for 2 hours. The medium was then poured into methanol and theprecipitate which formed was filtered and recrystallized from an ethylacetate/chloroform mixture.

In this manner, 0.042 mol of 3-chloro-2-(4-tosyloxybenzenesulphonyl)indane was obtained in a yield of 84%.

M.P.: 176° C.

b) 2-(4-Tosyloxybenzenesulphonyl)indene.

A mixture of 0.025 ml of 3-chloro-2-(4-tosyloxybenzenesulphonyl)indaneand 0.04 mol of triethylamine in 125 ml of chloroform was stirred for 4hours at room-temperature. The medium was poured into water anddistilled in the presence of chloroform. The organic phase was dried onsodium sulphate, filtered and concentrated. The green solid so obtainedwas recrystallized first from tetrahydrofuran and then from ethylacetate.

In this manner, 0.024 mol of 2-(4-tosyloxybenzenesulphonyl)indene wasobtained in the form of a white solid.

Yield: 82%

M.P.: 174° C.

c) 2-(4-Hydroxybenzenesulphonyl)indene.

A suspension of 0.01 mol of 2-(4-tosyloxybenzenesulphonyl)indene in 100ml of 2N-sodium hydroxide and 160 ml of ethanol was heated to 80° C.After complete dissolution, the reaction medium was poured into water,acidified with dilute hydrochloric acid and distilled in the presence ofdichloromethane. The residue was stirred in the presence of animalcharcoal and sodium sulphate and then filtered and concentrated.

In this manner 0.005 mol of 2-(4-hydroxybenzenesulphonyl)indene wasobtained in a yield of 52%.

M.P.: 209°-210° C. (ethyl acetate/hexane).

d)2-[4-{3-[N-methyl-N-(3,4-dimethoxy-β-phenethyl)amino]propyloxy}benzenesulphonyl)indeneoxalate.

A mixture of 0.005 mol of 2-(4-hydroxybenzenesulphonyl)indene and 3.5 gof crushed potassium carbonate in 10 ml of dimethylsulphoxide wasstirred for 30 min. After that, 0.006 mol of1-chloro-3-[N-methyl-N-(3,4-dimethoxy-β-phenethyl)amino]propane oxalatewas added while stirring was maintained for 24 hours atroom-temperature. The medium was poured into water and extracted withethyl ether. The ethereal solution was washed with water, dried onanhydrous sodium sulphate and filtered. The ethyl ether was eliminatedwith a rotary evaporator and the residue so obtained was purified bychromatography on a silica column. The base so provided was thentransformed into an oxalate by adding oxalic acid in ethyl ether.

In this manner2-[4-{3-[N-methyl-N-(3,4-dimethoxy-β-phenethyl)amino]propyloxy}benzenesulphonyl]indeneoxalate was obtained.

M.P.: 176° C. (ethanol/isopropanol).

EXAMPLE 34 Preparation of2-isopropyl-3-[4-{3-[N-methyl-N-(3,4-dimethoxybenzyl)amino]propyloxy}benzenesulphony]benzofuranacid oxalate (SR 33747 A)

a) 2-Isopropyl-3-[4-(3-bromopropyloxy)benzenesulphonyl) benzofuran

This compound was obtained using the method described in Example 15a.

M.P.: 111°-112° C.

Using the same procedure the following compounds were prepared:

COMPOUNDS

2-Isopropyl-3-[4-(2-bromoethoxy)benzenesulphonyl) benzofuran

M.P.: 109°-110° C.

2-Isopropyl-3-[4-(4-bromobutyloxy)benzenesulphonyl] benzofuran

Oily.

b)2-Isopropyl-3-[4-{3-[N-methyl-N-(3,4-dimethoxy-benzyl)amino)propyloxy}benzenesulphonyl]benzofuranacid oxalate

A mixture of 0.0103 mol of2-isopropyl-3-[4-(3-bromopropyloxy)benzenesulphony] benzofuran and0.0206 mol of N-methyl-3,4-dimethoxy-β-phenethylamine in 75 ml oftoluene was refluxed for 4 days in the presence of 0.03 mol of anhydrousand finely crushed potassium carbonate. After reacting the medium wasallowed to cool, the mineral salts were filtered out and the filtratewas evaporated to dryness. After that, the unreacted amine was separatedout by elution chromatography on neutral alumina using chloroform aseluent. The desired product was then purified by elution chromatographyon silica with acetone as eluent. The oil so isolated (yield: about 96%)was then transformed into an acid oxalate in ethyl acetate using anethereal solution of oxalic acid.

In this manner,2-isopropyl-3-[4-{3-[N-methyl-N-(3,4-dimethoxybenzyl)amino]propyloxy}benzenesulphonyl]benzofuran acid oxalate was obtained in a yield of 40 to 60%.

M.P.: 167° C. (ethanol).

Using the same method as that described above the following compoundswere prepared:

COMPOUNDS

2-Isopropyl-3-[4-{2-[N-methyl-N-(3,4-dimethoxy-benzyl)amino]ethyloxy}benzenesulphonylbenzofuran hemioxalate (SR 33752 A) (Example 35)

M.P.: 197° C. (methanol)

2-Isopropyl-2-[4-{3-[N-(3,4-dimethoxy-β-phenethyl)amino]propyloxy}benzenesulphonyl]benzofuranacid oxalate (SR 33753 A) (Example 36)

M.P.: 196° C. (methanol)

2-Isopropyl-3-[4-{2-[N-methyl-N-(3,4-dimethoxy-β-phenethyl)amino]ethyloxy}benzenesulphonylbenzofuran hemioxalate (SR 33754 A) (Example 37)

M.P.: 180° C. (methanol)

2-Isopropyl-3-[4-{4-[N-methyl-N-(3,4-dimethoxy-benzyl)amino]butyloxy}benzenesulphonyl]benzofuranhemioxalate (SR 33755 A) (Example 38)

M.P.: 154° C. (ethanol)

2-Isopropyl-3-[4-{4-[N-methyl-N-(3,4-dimethoxy-β-phenethyl)amino]butyloxy}benzenesulphonyl]benzofuranacid oxalate (SR 33756 A) (Example 39)

2-Isopropyl-3-[4-{3-[N-methyl-N-[(2-pyridyl)-β-ethyl]amino]propyloxy}benzenesulphonyl]benzofuran(SR 33783) (Example 40)

Yellow oil.

2-Isopropyl-3-[4-{3-[N-[3-(1,3-benzodioxolyl)]-β-ethyl]amino]propyloxy}benzenesulphonylbenzofuran acid oxalate (SR 33790 A) (Example 41)

M.P.: 194° C. (methanol)

EXAMPLE 42 Preparation of1-isopropyl-2-[4-{3-[N-methyl-N-(3,4-dimethoxy-β-phenethyl)amino]propyloxy}benzenesulphonyl]imidazoledihydrochloride (SR 33800 A)

a) 1-Isopropyl-2-(4-methoxybenzenesulphonyl) imidazole

Into 20 ml of acetonitrile was introduced 0.1 mol of1-isopropylimidazole.

After that 0.1 mol of 4-methoxybenzenesulphonyl chloride in 20 ml ofacetonitrile was added drop-by-drop. The addition took one hour and thetemperature increased to 35° C. After one hour stirring atroom-temperature 0.11 mol of triethylamine was added to the reactionmedium and stirring was maintained for 20 hours. The precipitate whichformed was suction-filtered, the filtrate was evaporated to dryness andthe residue was dissolved in ethyl acetate. After washing with neutralwater, the extract was dried and isolated to give 18.3 g of a brownishoil which was purified on a silica column. The elution with ethylacetate provided 4.5 g of a brownish oil which solidified.

In this manner, 1-isopropyl-2-(4-methoxybenzenesulphonyl) imidazole wasobtained in a yield of 16%.

Purity: 99.9% (high pressure liquid chromatography)

M.P.: 84°-86° C. (ethyl acetate/n-hexane 1/2)

Using the same procedure as that described above1-benzyl-2-(4-methoxybenzenesulphonyl) imidazole was obtained in theform of a white beige solid.

M.P.: 74.5° C. (ethyl acetate/n-hexane 1/2)

b) 1-Isopropyl-2-(4-hydroxybenzenesulphonyl) imidazole

In 30 ml of anhydrous N,N-dimethylformamide were suspended, undernitrogen atmosphere, 2.4 g (48×10⁻³ mol) of a 50%-sodium hydride oilymixture and 1.8 ml (24×10⁻³ mol) of 2-mercaptoethanol in 5 ml ofN,N-dimethylformamide was added. Stirring was maintained for one hour atroom-temperature and 3.85 g (11.7×10⁻³ mol) of1-isopropyl-2-(4-methoxybenzenesulphonyl) imidazole in 20 ml ofN,N-dimethylformamide were then added. The medium was then heated to140° C. for one hour, cooled and poured into 200 ml of iced water. Thebrownish precipitate which formed was eliminated by filtration and thefiltrate was acidified by adding concentrated hydrochloric acid. Themedium was then treated with sodium bicarbonate to neutrality and thefiltrate was evaporated to dryness. The brownish residual solid wastaken up in a dichloromethane/methanol 4/1 mixture and suction-filteredto eliminate the insoluble matter. The filtrate when concentratedprovided 4.75 g of a brownish oil.

In this manner, 2.3 g of 1-isopropyl-2-(4-hydroxybenzenesulphonyl)imidazole were obtained in the form of a slightly beige solid afterpurification on a silica column using ethyl acetate as eluent.

Yield: 74.2%.

Purity: 98.3% (high pressure liquid chromatography).

M.P.: 152°-153° C. (ethyl acetate/n-hexane 1/1)

Using the same procedure as that described above1-benzyl-2-(4-hydroxybenzenesulphonyl) imidazole was obtained in theform of a white solid.

Yield: 56.4%

M.P.: 161°-162° C. (ethyl acetate/methanol/n-hexane)

c)1-Isopropyl-2-[4-{3-[N-methyl-N-(3,4-dimethoxy-β-phenethyl)amino]propyloxy}benzenesulphonyl]imidazole dihydrochloride

In 23 ml of dimethysulphoxide were stirred for about 15 hours atroom-temperature, 2.3 g (8.6×10⁻³ mol) of1-isopropyl-2-(4-hydroxybenzenesulphonyl) imidazole, 3.45 g (9.5×10⁻³mol) of 1-chloro-3-[N-methyl-N-(3,4-dimethoxy-β-phenethyl)amino]propaneacid oxalate and 3 g (21.5×10⁻³ mol) of potassium carbonate. The mediumwas then heated for 5 hours at 60° C., poured into 100 ml of water andextracted with 3 fractions each of 50 ml of ethyl acetate.

The extracts were collected and washed with 3 fractions each of 30 ml ofwater to obtain 3.45 g of brownish oil. This oil was then purified on asilica column using an ethyl acetate/methanol 75/25 mixture as solventto provide 2.4 g of an oil. The dihydrochloride was then formed inmethanol by adding gaseous hydrochloric acid. The methanol wasevaporated off and the residue was taken up in dry ethyl ether andfiltered out.

In this manner, 2.05 g of1-isopropyl-2-[4-{3-[N-methyl-N-(3,4-dimethoxy-β-phenethyl)amino]propyloxy}benzenesulphonyl]imidazoledihydrochloride were obtained in the form of a white solid.

Yield: 41.4%

Purity: 98.4%

M.P.: 90° C.

Using the same procedure as that described above1-benzyl-2-[4-{3-[N-methyl-N-(3,4-dimethoxy-β-phenethyl)amino]propyloxy}benzenesulphonyl]imidazole acid oxalate was obtained in the form of a white solid (SR33776 A) (Example 43).

Yield: 49.21%

M.P.: 130.5° C. (ethyl acetate/methanol)

EXAMPLE 44 Preparation of4-[4-{3-[N-methyl-N-(3,4-dimethoxy-β-phenethyl)amino]propyloxy}benzenesulphonyl]-1,5,diphenyl-imidazole acid oxalate

a) 4-(4-Methoxy-benzenesulphonyl)-1,5-diphenyl-imidazole

While stirring at room-temperature, a solution of 2.1 g (0.01 mol) of(4-methoxy-benzene)sulphonylmethylisocyanide and 2.1 g (0.01 mol) ofN-phenylbenzimidoyl chloride in 25 ml of dimethoxyethane was addeddrop-by-drop and under nitrogen atmosphere to a suspension of 0.4 g(0.01 mol) of 60%-sodium hydride in 25 ml of dimethylsulphoxide. Afterthe introduction, stirring was maintained for 0.75 hour and the mediumwas slowly poured into iced water. An amorphous product was so obtainedwhich transformed into an oil. This oil was then purified on a neutralalumina column.

In this manner, 0.774 g of4-(4-methoxy-benzenesulphonyl)-1,5-diphenylimidazole was obtained in ayield of 20%.

M.P.: 157° C.

b) 4-(4-Hydroxy-benzenesulphonyl)-1,5-diphenyl-imidazole

To a solution of 0.287 g (3.7×10⁻³ mol) of 2-mercapto-ethanol in 5 ml ofN,N-dimethylformamide was added, under stirring and by little fractions,0.354 g of 60%-sodium hydride. Stirring was maintained for 0.25 hour atroom-temperature and then 0.774 g of4-(4-methoxy-benzenesulphonyl)-1,5-diphenyl-imidazole in 5 ml ofN,N-dimethylformamide was added. The reactor was heated for 1 hour in anoily bath at 140° C. and the medium was allowed to cool, poured into 30ml of iced water and acidified to pH=5 with concentrated hydrochloricacid. The precipitate which formed was suction-filtered, washed withwater and dried on phosphorous pentoxide under 5 mm Hg. The solidobtained was then washed with ethyl acetate.

In this manner, 0.617 g of4-(4-hydroxy-benzenesulphonyl)-1,5-diphenyl-imidazole was provided in ayield of 91%.

M.P.: 300° C.

c) 4-[4-{3-[N-methyl-N-(3,4-dimethoxy-β-phenethyl)amino]propyloxy}benzenesulphonyl-1,5-diphenyl-imidazole acid oxalate

To 0.60 g (1.6×10⁻³ mol) of4(4-hydroxy-benzenesulphonyl)-1,5-diphenyl-imidazole in 17 ml ofN,N-dimethylformamide was added 0.730 g (5.28×10⁻³ mol) of crushedanhydrous potassium carbonate. The medium was stirred for 0.5 hour atroom-temperature. After that 0.578 g (1.6×10⁻³ mol) of1-chloro-3-[N-methyl-N-(3,4-dimethoxy-β-phenethyl)amino] propane acidoxalate was added and the reactor was heated in an oily bath at 105° C.for 0.75 hour. After cooling, the mixture was poured into iced water andthe precipitate which formed was suction-filtered. This solid whichtransformed into an oil was chromatographied on a silica column usingmethanol as an eluent. An amorphous product was so obtained (M.P.: <50°C.) which was transformed into an oxalate in an ethyl ether/ethylacetate mixture using an ethereal solution of oxalic acid.

In this manner,4-[4-{3-[N-methyl-N-(3,4-dimethoxy-β-phenethyl)amino]propyloxy}benzenesulphonyl-1,5-diphenyl-imidazole acid oxalate was obtained. M.P.:162° C. (isopropanol/ethanol/methanol).

EXAMPLE 45 Preparation of4-[4-{3-[N-methyl-N-(3,4-dimethoxy-β-phenethyl)amino]propyloxy}benzenesulphonyl-5-phenyl-thiazole acid oxalate (SR 33791 A)

a) 4-(4-Methoxybenzenesulphonyl)-5-phenyl-thiazole

To 6.3 g (0.03 mol) of (4-methoxybenzene) sulphonylmethylisocyanide and3.2 g (0.015 mol) of S-(thiobenzoyl) thioglycolic acid in 210 ml oftert-butanol, were added, at 19° C. and in 5 min., 2.6 g (0.046 mol) ofcrushed potassium hydroxide. Stirring was then maintained for 5.5 hoursat room-temperature. After that, the tert-butanol was evaporated offunder vacuum and a saturated solution of sodium chloride was added tothe residue. The medium was extracted with a dichloromethane diethylether mixture, washed, dried on anhydrous sodium sulphate andevaporated. The residue was then purified by chromatography on a silicacolumn using dichloroethane as eluent.

In this manner 2.2 g of 4-(methoxybenzenesulphonyl)-5-phenyl-thiazolewere obtained in the form of a yellow solid.

Yield: 44%

M.P.: 130° C. (methanol)

b) 4-(4-Hydroxybenzenesulphonyl)-5-phenyl-thiazole

A mixture of 1.1 g (3.3×10⁻³ mol) of4-(4-methoxybenzenesulphonyl)-5-phenyl-thiazole in a mixture of 33 ml ofglacial acetic acid and 33 ml of 47%-hydrobromic acid was heated underreflux for 35 hours. The medium was evaporated to dryness under vacuumand water was added to the residue followed by sodium bicarbonate. Thegrey precipitate which formed was suction-filtered and taken up indichloroethane. The phenol derivative was extracted with an aqueoussolution of 0.01 mol of sodium hydroxide and regenerated byacidification using acetic acid.

In this manner, 0.7 g of 4-(4-hydroxybenzenesulphonyl)-5-phenyl-thiazolewas obtained in a yield of 66%.

M.P.: 195° C.

c)4-[4-{3-[N-methyl-N-(3,4-dimethoxy-β-phenethyl)amino]propyloxy}benzenesulphonyl]-5-phenyl-thiazoleacid oxalate

To a solution of 0.75 g (2.4×10⁻³ mol) of4-(4-hydroxybenzenesulphonyl)-5-phenyl-thiazole in 25 ml ofN,N-dimethylformamide, was added 1.1 g (7.9×10⁻³ mol) of crushedanhydrous potassium carbonate. The medium was stirred for 0.5 hour atroom-temperature and 0.867 g (2.4×⁻³ mol) of1-chloro-3-[N-methyl-N-(3,4-dimethoxy-β-phenethyl)amino] propane acidoxalate was added. The reaction mixture was heated at 105° C. for 0.75hour, cooled and poured into iced water. After extraction with ethylether, the organic layer was washed with water and dried on anhydroussodium sulphate. After evaporation to dryness under vacuum, the oilyresidue was chromatographied on a silica column using ethanol as eluent.The fractions were collected and evaporated to dryness to provide anoily product which was taken up in a dry ethyl ether/ethyl acetatemixture. The acid oxalate was then formed by adding oxalic acid in ethylether.

In this manner, 0.8 g of4-[4-{3-[N-methyl-N-(3,4-dimethoxy-β-phenethyl)amino]propyloxy}benzenesulphonyl]-5-phenyl-thiazoleacid oxalate was obtained after recrystallization from methanol.

M.P.: 161.8° C.

EXAMPLE 46 Preparation of4-[4-{3-[N-methyl-N-(3,4-dimethoxy-β-phenethyl)amino]propyloxy}benzenesulphonyl]-5-isopropyl-pyrazoleacid oxalate (SR33801A)

a)1-Isobutyroyl-1-(4-tosyloxy-benzenesulphonyl)-2-N,N-dimethylamino-ethene

A solution of 9.9 g (0.025 mol) of1-(4-tosyloxy-benzenesulphonyl)-3-methyl-2-butanone (M.P.: 156°-157° C.)and 7.5 g (0.0625 mol) of N,N-dimethylformamide dimethylacetal in 50 mlof toluene was heated under reflux for 18 hours. After reacting, themedium was evaporated to dryness and the residue was stirred togetherwith 50 ml of cyclohexane for 1.5 hour. The medium was suction-filtered,washed with cyclohexane and the product so obtained was recrystallizedfrom 23 ml of methanol.

In this manner, 5.2 g of1-isobutyroyl-1-(4-tosyloxy-benzenesulphonyl)-2-N,N-dimethylamino-ethenewere obtained in the form of crystals.

Yield: 65.5%.

Purity: 92.01% (high pressure liquid chromatography).

M.P.: 115°-116° C.

b) 4-(4-Hydroxy-benzenesulphonyl)-5-isopropyl-pyrazole

A solution of 4.5 g (0.01 mol) of1-isobutyroyl-1-(4-tosyloxybenzenesulphonyl)-2-N,N-dimethylamino-etheneand 16 ml (0.2 mol) of hydrazine hydrate in 25 ml of methanol and 7 mlof water was heated under reflux for 1 hour. After reacting, the mediumwas evaporated to dryness and the residue was purified by elutionchromatography on silica using ethyl acetate as eluent. The oil soobtained was then crystallized from 100 ml of water and recrystallizedalso from water.

In this manner, 0.9 g of4-(4-hydroxy-benzenesulphonyl)-5-isopropyl-pyrazole was obtained in ayield of 33.7%. Purity: 98% (High pressure liquid chromatography).

M.P.: 177°-179° C.

c)4-[4-{3-[N-methyl-N-(3,4-dimethoxy-β-phenethyl)amino]propyloxy}benzenesulphonyl]-5-isopropyl-pyrazoleacid oxalate

A mixture of 0.01 mol of 4-(4-hydroxy-benzenesulphonyl)-5-isopropylpyrazole, 0.01 mol of1-chloro-3-[N-methyl-N-(3,4-dimethoxy-β-phenethyl)amino] propane in 40ml of dimethylsulphoxide and 0.028 mol of anhydrous and finely crushedpotassium carbonate was stirred for 3 days at room-temperature. Afterreacting, the medium was poured into a mixture of 100 ml of water and100 g of ice. After extraction with 3 fractions each of 100 ml ofisopropyl ether the organic layer was washed with 50 ml of water. Theoily residue was then purified by elution chromatography on silicaneutralized with diethylamine and using acetone as eluent. The acidoxalate was then formed in isopropyl ether using an ethereal solution ofoxalic acid.

In this manner,4-[4-{3-[N-methyl-N-(3,4-dimethoxy-β-phenethyl)amino]propyloxy}benzenesulphonyl]-5-isopropyl-pyrazoleacid oxalate was obtained.

EXAMPLE 47 Preparation of4-[4-{3-[N-methyl-N-(3,4-dimethoxy-β-phenethyl)amino]propyloxy}benzenesulphonyl]-5-isopropyl-isoxazole

a)1-Isobutyroyl-1-(4-methoxy-benzenesulphonyl)-2-N,N-dimethylamino-ethene

This compound was obtained from1-(4-methoxy-benzenesulphonyl)-3-methyl-2-butanone (M.P.: 48°-49.5° C.)using the same procedure as that described in Example 35.

Yield: 80.9%.

M.P.:

1) 63°-66° C.

2) 66°-71° C.

b) 5-Isopropyl-4-(4-methoxy-benzenesulphonyl)-isoxazole

A mixture of 12.45 g (0.04 mol) of1-(4-methoxy-benzenesulphonyl)-2-N,N-dimethylamino-ethene, 3.32 g (0.04mol) of anhydrous sodium acetate and 2.8 g (0.04 mol) of hydroxylaminehydrochloride in 160 ml of methanol and 80 ml of water was stirred for22 hours at room-temperature. After reacting, the medium was poured into200 ml of water and the mixture was stirred for 0.5 hour at 10° C. Theproduct so obtained was suction-filtered, washed with water and driedunder vacuum at room-temperature.

In this manner 7.1 g of5-isopropyl-4-(4-methoxy-benzenesulphonyl)isoxazole were obtained in ayield of 63%.

M.P.: 62°-63.5° C.

c) 5-Isopropyl-4-(4-hydroxy-benzenesulphonyl)-isoxazole

A mixture of 16.7 g (0.06 mol) of5-isopropyl-4(4-methoxybenzenesulphonyl)-isoxazole and 32 g (0.24 mol)of aluminum chloride in 400 ml of dichloroethane was heated under refluxfor 6 hours. After reaction the medium was allowed to cool and thenpoured into 510 g of ice and 500 ml of water. The mixture was stirredfor 0.5 hours, decanted, washed to neutrality and evaporated undervacuum. The residue was dissolved in 400 ml of ethanol, discolored with6 g of active charcoal, filtered and evaporated. The product so providedwas purified by elution chromatography on silica using isopropyl etheras eluent.

In this manner, 8.6 g of5-isopropyl-4-(4-hydroxy-benzenesulphonyl)isoxazole were obtained afterrecrystallization from 55 ml of toluene.

Yield: 53.6%.

M.P.: 129°-131° C.

d)4-[4-{3-[N-methyl-N-(3,4-dimethoxy-β-phenethyl)amino]propyloxy}benzenesulphonyl]-5-isopropyl-isoxazole

This compound was obtained using the same method as that described inExample 46. M.P. of the acid oxalate: 158.3° C. (methanol).

EXAMPLE 48 Preparation of4-[4-{3-[N-methyl-N-(3,4-dimethoxy-β-phenethyl)amino]propyloxy}benzenesulphonyl]-5-isopropyl-3-phenyl-isoxazole

a) 5-Isopropyl-3-phenyl-4-(4-tosyloxy-benzenesulphonyl)-isoxazole

To a solution of 0.23 g (0.01 at.gr) of sodium in 15 ml of methanol,were added, by small fractions, 3.95 g (0.01 mol) of1-(4-tosyloxy-benzenesulphonyl)-3-methyl-2-butanone while maintainingthe temperature at 10° C. At the same temperature, 1.55 g (0.01 mol) ofbenzhydroxamic acid chloride in 15 ml of methanol was added drop-by-dropin 20 minutes. The mixture was still stirred for 1 hour at 10° C. andthe temperature was then allowed to increase to 20° C. while stirringfor 4 hours. The medium was evaporated to dryness and the residue wassuction-filtered and washed with water. The crude product so obtainedwas recrystallized from about 180 ml of ethanol and then purified byelution chromatography on silica using chloroform as eluent.

In this manner, 2.65 g of5-isopropyl-3-phenyl-4-(4-tosyloxybenzenesulphonyl)-isoxazole wereobtained in a yield of 53.2%.

Purity: 38.4% (high pressure liquid chromatography)

M.P.: 147.5°-149° C.

b) 4-(4-Hydroxy-benzenesulphonyl)-5-isopropyl-3-phenyl-isoxazole

A mixture of 2.5 g (0.005 mol) of5-isopropyl-3-phenyl-4-(4-tosyloxybenzenesulphonyl)-isoxazole and 0.8 g(0.02 mol) of sodium hydroxide in 20 ml of isopropanol and 10 ml ofwater was heated under reflux for 2.5 hours. After reacting, the mixturewas allowed to cool, diluted with 50 ml of water and acidified withconcentrated hydrochloric acid. The product so obtained wassuction-filtered and washed with water to obtain 1.4 g of the desiredcompound which was purified by elution chromatography on silica usingchloroform as eluent.

In this manner, 1.12 g of4-(4-hydroxy-benzenesulphonyl)-5-isopropyl-3-phenyl-isoxazole wasobtained in a yield of 65.9%.

M.P.: 173°-174.5° C.

c)4-[4-{3-[N-methyl-N-(3,4-dimethoxy-β-phenethyl)amino]propyloxy}benzenesulphonyl]-5-isopropyl-3-phenyl-isoxazole

This compound was obtained following the method described in Example 46.

EXAMPLE 49 Preparation of2-[4-{3-[N-methyl-N-(3,4-dimethoxy-β-phenethyl)amino]propyloxy}benzenesulphonyl}-naphthaleneacid oxalate (SR 33732A)

a) 2-Benzenesulphonate-naphthalene

A solution of 510 ml of 25%-aqueous solution of potassium carbonate wasadded to a mixture of 60 g (0.264 mol) of 2-naphthalenesulfonyl chlorideand 0.264 mol of phenol in 600 ml of acetone. A precipitate formed. Themedium was stirred for about 15 hours at room-temperature and thenfiltered. After washing first with 1%-sodium hydroxide solution and thenwith water, the medium was dried and recrystallized from methanol.

In this manner, 2-benzenesulphonate-naphthalene was obtained in a yieldof 84%.

M.P.: 98° C.

b) 2-(4-Hydroxy-benzenesulphonyl)naphthalene

To 70 ml of nitrobenzene and 2 equivalents of aluminum chloride wereadded 20 g of 2-benzenesulphonate naphthalene. The mixture was heated to120°-140° C. for about 2.5 hours and became black. The medium was thendecomposed using a hydrochloric acid/ice mixture. After decantation, thedried organic layer was purified on a silica column using adichloromethane/heptane 5/5 mixture. The nitrobenzene was eliminated andthe product was eluted with a dichloromethane/heptane 7/3 mixture. Theoily compound so obtained was triturated with ethyl ether, crystallizedand filtered.

In this manner, 2-(4-hydroxy-benzenesulphonyl)-naphthalene was obtained.

M.P.: 170° C.

c)2-[4-{3-[N-methyl-N-(3,4-dimethoxy-β-phenethyl)amino]propyloxy}benzenesulphonyl]-naphthaleneacid oxalate

A mixture of 1.4 g of 2-(4-hydroxy-benzenesulphonyl)-naphthalene, 5equivalents of potassium carbonate and 1.5 equivalent of1-chloro-3-[N-methyl-N(3,4-dimethoxy-β-phenethyl)amino]propane acidoxalate in 5 ml of dimethylsulphoxide was heated on a water-bath at30°-35° C. for 15 hours. After that, 10 ml of water were added and themedium was extracted with dichloromethane and decanted. The organiclayer was dried and purified on a silica column using firstdichloromethane and then a dichloromethane/methanol 98/2 mixture aseluents.

In this manner,2-[4-{3-[N-methyl-N-(3,4-dimethoxy-β-phenethyl)amino]propyloxy}benzenesulphonyl]-naphthaleneacid oxalate was obtained in a yield of 75%.

M.P.: 164° C. (ethanol)

EXAMPLE 50 Preparation of1-[4-{3-[N-methyl-N-(3,4-dimethoxy-β-phenethyl)amino]propyloxy}benzenesulphonyl]cyclohexaneacid oxalate (SR 33767 A)

a) 2-lodo-1-(4-tosyloxybenzenesulphonyl) cyclohexane

This compound was obtained following the method described in Example 33a) but replacing sulphonyl chloride by sulphonyl iodide and heating at40° C. for 4 hours.

Yield: 40%

M.P.: 109° C.

b) 1-(4-Tosyloxybenzenesulphonyl) cyclohexane

This compound was obtained following the method described in Example 33b).

Yield: 80%.

M.P.: 110° C.

c) 1-(4-Hydroxybenzenesulphonyl) cyclohexane

This compound was obtained following the method described in Example 33c).

M.P.: 120° C.

d)1-[4-{3-[N-methyl-N-(3,4-dimethoxy-β-phenethyl)amino]propyloxy}benzenesulphonyl]cyclohexaneacid oxalate

Yield: 65%.

M.P.: 174° C.

EXAMPLE 51 Preparation of2-isopropyl-3-[4-{3-[N-methyl-N-(3,4-dimethoxy-β-phenethyl)amino]propyloxy}benzenesulphonyl]indolehemioxalate (SR 33738 A)

a) 2-isopropyl-3-(4-methoxy-benzenesulphonyl) indole

A solution of 1.4 g (5×10⁻³ mol) of 2-isopropyl-3-(4-methoxy-phenylthio)indole (prepared from 2-isopropylindole and 4-methoxythiophenol in thepresence of iodine) in 25 ml of dichloromethane was stirred and cooledto about -5° C. After that 2.6 g (15×10⁻³ mol) of 3-chloroperbenzoicacid in 25 ml of dichloromethane was added drop-by-drop. The temperaturewas then allowed to return to room-temperature and the stirring wasmaintained for 2 hours. The reaction product was washed with a dilutedsodium hydroxide solution and then twice with water. The medium wasdried on anhydrous sodium sulphate, filtered and the solvent wasevaporated off.

In this manner, 1.3 g of 2 isopropyl-3-(4-methoxy-benzenesulphonyl)indole was obtained after recrystallization from toluene.

M.P.: 178° C.

Using the same procedure as that described above,3-isopropyl-2-(4-methoxy-benzenesulphonyl)indole was prepared.

Yield: 90%.

M.P.: 124° C.

b) 2-Isopropyl-3-(4-hydroxy-benzenesulphonyl)indole

To a solution of 3.3 g (0.01 mol) of2-isopropyl-3-(4-methoxybenzenesulphonyl)indole in 20 ml ofN,N-dimethylformamide was added a solution of 0.024 mol of a50%-suspension sodium hydride and 0.012 mol of 2-mercaptoethanol in 10ml of N,N-dimethylformamide. The medium was heated to 135° C. for 4hours and cooled. After that a solution of 0.016 mol of sodium hydrideand 0.008 mol of 2-mercapto-ethanol was again added and the mixture wasagain heated at 135° C. for 3 hours. The reaction medium was then takenup in 50 ml of water, acidified, extracted with ethyl ether and purifiedby chromatography on silica.

In this manner, 3.6 g of 2-isopropyl-3-(4-hydroxy-benzenesulphonyl)indole were obtained in oily form and the product was crystallized froman ethanol/water mixture.

Yield; 82%.

M.P.: 152° C.

Using the same procedure as that described above,3-isopropyl-2-(4-hydroxy-benzenesulphonyl)indole was prepared.

Yield: 46.9%.

M.P.: about 72° C.

c)2-Isopropyl-3-[4-{3-[N-methyl-N-(3,4-dimethoxy-β-phenethyl)amino]propyloxy}benzenesulphonyl]indolehemioxalate

This compound was obtained in accordance with Example 15.

Yield: 50%.

M.P.: about 115° C. (isopropanol/ethyl ether)

Using the same procedure as that described above the following compoundswere prepared:

Compounds

2-Isopropyl-3-{4-[3-(di-n-butylamino)propyloxy]benzenesulphonyl}indoleacid oxalate (SR 33743 A) (Example 52)

Yield: 79.4%.

M.P.: about 85° C. (ethylacetate/isopropanol 8/2).

2-Isopropyl-3-[4-{3-[N-methyl-N-(3,4-dimethoxy-β-phenethyl)amino]propyloxy}phenylthio]indolehemioxalate (SR 33737 A) (Example 53) [from2-isopropyl-3-(4-hydroxy-phenylthio)indole]

M.P. 134° C. (isopropanol/ethyl ether)

3-Isopropyl-2-[4-{3-N-methyl-N-(3,4-dimethoxy-β-phenethyl)amino]propyloxy}benzenesulphonyl]indoleacid oxalate (SR 33807 A) (Example 54).

Yield: 42.2%.

M.P.: about 105° C.

EXAMPLE 55 Preparation of1-methyl-2-isopropyl-3-[4-{3-[N-methyl-N-(3,4-dimethoxy-β-phenethyl)amino]propyloxy}benzenesulphony]indole(SR 33741)

a) 1-Methyl-2-isopropyl-3-(4-methoxy-benzenesulphonyl)indole

A solution of 6.6 g (0.02 mol) of2-isopropyl-3-(4-methoxybenzenesulphonyl)indole in 30 ml ofhexamethylphosphotriamide was cooled to about 0° C. and 1 g (0.022 mol)of a 55%-suspension of sodium hydride was added by small fractions.After the hydrogen evolution was terminated 2.8 g (0.02 mol) of methyliodide were introduced. The stirring was maintained at room-temperaturefor 12 hours and the medium was poured into water and extracted withethyl ether. The ethereal phase was washed with water, dried onanhydrous sodium sulphate and filtered. The ether was then evaporatedoff.

In this manner, 5.4 g of1-methyl-2-isopropyl-3-(4-methoxybenzenesulphonyl)indole were obtainedafter recrystallization from isopropanol/hexane 1/1.

Yield: 78.7%.

M.P.: 125° C.

Using the same procedure as that described above,1-methyl-3-isopropyl-2-(4-methoxy-benzenesulphonyl)indole was prepared.

Yield: 85%.

M.P.: 125° C. (hexane/isopropanol 9/1)

b) 1-Methyl-2-isopropyl-3-(4-hydroxy-benzenesulphonyl)indole

This compound was obtained according to Example 51b).

Yield: 87%.

M.P.: 202° C.

Using the same procedure as that described above,1-methyl-3-isopropyl-2-(4-hydroxy-benzenesulphonyl)indole was prepared.

Yield: 45.9%.

M.P.: 185° C. (dichloroethane/ethyl acetate 9/1).

c)1-Methyl-2-isopropyl-3-[4-{3-[N-methyl-N-(3,4-dimethoxy-β-phenethyl)amino]propyloxy}benzenesulphonyl]indole

This compound was obtained according to Example 57c).

Yield: 75%.

M.P.: 96° C. (isopropanol/diisopropylether 4/6).

Using the same procedure as that described above, the followingcompounds were prepared:

Compounds

1-Methyl-2-isopropyl-3-{4-[3-(di-n-butylamino)propyloxy]benzenesulphonyl}indoleacid oxalate (SR 33744 A) (Example 56)

Yield: 80%.

M.P.: about 90° C. (isopropanol)

1-Methyl-2-isopropyl-3-[4-{3-[N-methyl-N-(3,4-dimethoxy-benzyl)amino]propyloxy}benzenesulphonyl]indoleacid oxalate (SR 33768 A) (Example 57)

Yield: 62%.

M.P.: about 105° C. (isopropanol)

EXAMPLE 58 Preparation of1-methyl-2-isopropyl-3-[4-{3-(tert-butylamino)propyloxy}benzenesulphonyl]indole(SR 33770)

To a solution of 2.8 g (0.0085 mol) of1-methyl-2-isopropyl-3-(4-hydroxybenzenesulphonyl)indole in 100 ml ofN,N-dimethylformamide were added 14 g of anhydrous and crushed potassiumcarbonate. After that 6.8 g (0.037 mol) of 1,3-dibromopropane were addedand the medium was heated at 100° C. for 0.5 hour. The mixture waspoured into water, extracted with ethyl ether and the ethereal fractionwas washed with water, dried on anhydrous sodium sulphate, filtered andevaporated to obtain 2.7 g of1-methyl-3-[4-(3-bromo-propoxy)benzenesulphonyl]-2-isopropyl-indole(yield: 69%). This crude bromopropoxy derivative was dissolved in 60 mlof dimethylsulphoxide and 2.2 g (0.03 mol) of tert-butylamine wereadded. The medium was then stirred at room-temperature for 48 hours,poured into water and extracted with ethyl ether. The ethereal solutionwas then washed with water, dried on anhydrous sodium sulphate, filteredand evaporated. The crude product so obtained (2.3 g) was then purifiedby chromatography on a silica column (solvent: methanol).

In this manner, 1.4 g of1-methyl-2-isopropyl-3-[4-{3-(tert-butylamino)propyloxy}benzenesulphonyl]indolewas obtained after recrystallization from a heptane/isopropanol 1/1mixture.

Yield: 42.3%.

M.P.: 145° C.

Using the same procedure as that described above,1-methyl-3-isopropyl-2-[4-{3-[N-methyl-N-(3,4-dimethoxy-β-phenethyl)amino]propyloxy}benzenesulphonyl]indoleacid oxalate was prepared (SR 33805 A) (Example 59).

Yield: 60.8%.

M.P.: about 94° C. (ethyl acetate/isopropanol/diisopropyl ether).

EXAMPLE 60 Preparation of2-isopropyl-1-{4-}3-[-N-methyl-N-(3,4-dimethoxy-β-phenethyl)amino]propyloxy}benzenesulphonyl]benzeneacid oxalate (SR 33718A)

a) Sodium 2-isopropyl-benzenesulphonate

To a solution of 36.5 g (0.268 mol) of 2-isopropyl-phenol, 40 g (0.268mol) of N,N-dimethylthiocarbamoyl chloride and 3.1 g (0.013 mol) oftriethylbenzylammonium chloride in 270 ml of toluene was added, at 15°C., a solution of 27 g (0.67 mol) of sodium hydroxide in 130 ml ofwater. The stirring was maintained at this temperature for 2 hours. Theorganic fraction was then washed with water and the toluene wasevaporated off. An oil residue was obtained which was purified bydistillation under vacuum (138°-140° C.; 0.5 mm Hg) to provide 34 g of2-isopropyl O-phenyl-dimethylthiocarbamate. This product was thensubmitted to a transposition reaction by heating at 300° C. for 3 hours.The crude 2-isopropyl S-phenylthiocarbamate so obtained was then takenup in 600 ml of formic acid. To the solution so obtained and at atemperature at 15° C., were then added 225 ml of 30%-hydrogen peroxide.The stirring was maintained for about 12 hours. The formic acid was thendistilled under reduced pressure, the oily residue was taken up in waterand sodium hydroxide was added to pH=9. The water was eliminated and theresidue was recrystallized from 200 ml of boiling water. Thecrystallization was rendered complete by adding sodium chloride and theprecipitate so obtained was dried under vacuum at 60° C.

In this manner 24.6 g of sodium 2-isopropyl-benzenesulphonate wereobtained.

Yield: 70.7%.

Using the same procedure as that described above sodium2-ethylbenzenesulphonate (yield: 100%) was prepared from 2-ethylO-phenyldimethylthiocarbamate (B.P.: 130°-132° C.; 1 mm Hg).

b) 2-Isopropyl-1-(4-methoxybenzenesulphonyl)-benzene

A mixture of 110 ml of methanesulphonic acid and 11 g of phosphoricanhydride was heated to about 80° C. to complete dissolution of theanhydride. After cooling to room-temperature, 9.5 g (0.0425 mol) ofsodium 2-isopropylbenzenesulphonate and 4.6 g (0.0425 mol) of anisolewere added. The medium was heated at 80° C. for 2 hours, cooled toroom-temperature and poured onto ice. After extraction with ethyl ether,the ethereal fraction was washed with water, dried on anhydrous sodiumsulphate and filtered. The ether was eliminated to obtain 9.8 g of crudeproduct which was purified by chromatography on a silica column(solvent: dichloroethane).

In this manner, 5.2 g of2-isopropyl-1-(4-methoxy-benzenesulphonyl)-benzene was obtained, afterrecrystallization from heptane/isopropanol 95/5.

Yield: 42.2%

M.P.: 100° C.

Using the same procedure as that described above,2-ethyl-1-(4-methoxybenzenesulphonyl)-benzene was obtained.

Yield: 66.6%

M.P.: 71° C.

c) 2-Isopropyl-1-(4-hydroxy-benzenesulphonyl)-benzene

A mixture of 4.2 g (0.0145 mol) of2-isopropyl-1-(4-methoxy-benzenesulphonyl)-benzene and 42 g of pyridinehydrochloride was heated at 220° C. for 0.5 hour. After cooling, themedium was taken up in water and extracted with dichloroethane. Thedichloroethane solution was then washed with water and dried onanhydrous sodium sulphate and filtered. The solvent was then eliminatedunder vacuum to obtain a product which was recrystallized from an ethylacetate/heptane 2/8 mixture.

In this manner 3.2 g of2-isopropyl-1-(4-hydroxy-benzenesulphonyl)-benzene were obtained in ayield of 80%.

M.P.: 160° C.

Using the same procedure, 2-ethyl-1-(4-hydroxy-benzenesulphonyl)-benzenewas prepared in a yield of 83%

M.P.: 158° C. (heptane/isopropanol 95/5).

d)2-Isopropyl-1-[4-{3-[N-methyl-N-(3,4-dimethoxy-β-phenethyl)amino]propyloxy}benzenesulphonyl]benzeneacid oxalate.

This compound was obtained following the same procedure as thatdescribed in Example 9b.

Yield: 79%

M.P.: 120° C.

Using the same procedure as that described above, the compoundshereunder were prepared:

2-Isopropyl-1-{4-[3-(di-n-butylamino)propyloxy]benzenesulphonyl}benzeneacid oxalate (SR 33722A) (Example 61)

Yield: 88.8%

M.P.: 88° C. (ethyl acetate)

2-Ethyl-1-[4-{3-[N-methyl-N-(3,4-dimethoxy-β-phenethyl)amino]propyloxy}benzenesulphonyl]benzeneacid oxalate (SR 33735A) (Example 62)

Yield: 77.8%

M.P.: 175° C. (isopropanol)

2-Ethyl-1-{4-[3-(di-n-butylamino)propyloxy]benzenesulphonyl}benzene acidoxalate (SR 33740A) (Example 63)

Yield: 72.4%

M.P.: about 80° C. (isopropanol/ethyl ether).

EXAMPLE 64 Preparation of2-isopropyl-1-[4-{3-(tert-butylamino)propyloxy}benzenesulphonyl]benzeneacid oxalate (SR 33728A)

a) 2-Isopropyl-1-[4-(3bromo-propyloxy)benzenesulphonyl]benzene.

While stirring 11.6 g of anhydrous and crushed potassium carbonate wasadded to 2 g (0.0072 mol of 2-isopropyl-1-(4-hydroxy-benzenesulphonyl)benzene in 100 ml of N,N-dimethylformamide. After that, 5.8 g (0.0288mol) of 1,3-dibromopropane were added and the whole was heated at 100°C. for 0.5 hour. The medium was cooled, poured into water and extractedwith ethyl ether. The ethereal layer was washed with water, dried onanhydrous sodium sulphate and filtered. The ether was then eliminatedand the residue was purified by chromatography on a silica column usinga dichloroethane/hexane 6/4 mixture.

In this manner, 2.4 g of2-isopropyl-1-[4-(3-bromopropyloxy)benzenesulphonyl]benzene wereobtained in oily form.

Yield: 84%

n_(D) ²⁵ : 1.558

Using the same procedure as that described above,2-ethyl-1-[4-(3-bromopropyloxy)benzenesulphonyl]benzene was obtained ina quantitative yield.

b)2-Isopropyl-1-[4-{3-(tert-butylamino)propyloxy}benzenesulphonyl]benzeneacid oxalate.

A mixture of 2.5 g (0.00629 mol) of2-isopropyl-1-[4-(3-bromopropyloxy)benzenesulphonyl]benzene, 2.26 g(0.031 mol) of tert-butylamine and 25 ml of dimethylsulphoxide wasstirred at room-temperature for 48 hours. The medium was then pouredinto water and extracted with ethyl ether. The ethereal fraction waswashed with water, dried on anhydrous sodium sulphate and filtered. Theether was eliminated to obtain 2.4 g of a base of which the acid oxalatewas formed in ether medium.

In this manner, 1.8 g of2-isopropyl-1-[4{3-(tert-butylamino)propyloxy}benzenesulphonyl]benzeneacid oxalate was obtained after recrystallization from ethylacetate/isopropanol 7/3.

Yield: 60%

M.P.: 116° C.

Using the same procedure2-ethyl-1-[4-{3-(tert-butylamino)propyloxy}benzenesulphonyl]benzene acidoxalate was prepared (SR 33763A) (Example 65)

Yield: 43.1%

M.P.: 203.7° C. (isopropanol)

EXAMPLE 66 Preparation of5-(2-chloro-benzyl)-2-ethyl-3-[4-{3-N-methyl-N-(3,4-dimethoxy-β-phenethyl)amino]propyloxy}benzenesulphonyl]-4,5,6,7-tetrahydrothienol[3,2-c]pyridineoxalate (SR 33785A)

a)5-(2-Chloro-benzyl)-2-ethyl-3-(4-hydroxy-benzenesulphonyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine

A mixture of 13.5 g (0.046 mol) of5-(2-chloro-benzyl)-2-ethyl-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine and29.4 g (0.047 mol) of sodium benzyloxybenzenesulphonate was heated at60° C. for 16 hours together with a solution of 20 g of phosphorouspentoxide in 200 ml of anhydrous methanesulphonic acid. The medium wascooled and water was added. After that the mixture was neutralized byadding sodium hydroxide to pH=7.

After extraction with dichloroethane, the dichloroethane fraction waswashed with water, dried on anhydrous sodium sulphate and filtered. Thedichloroethane was distilled off and the oil residue (25 g) wasdissolved in 300 ml of ethanol. After that, 20 ml of 30%-sodiumhydroxide were added and the medium was heated at 80° C. for 4 hours.The ethanol was eliminated and the residue was taken up in water. Themedium was treated with active charcoal, filtered and neutralized withacetic acid. After filtration, the product was washed on the filter withwater and dried under vacuum at 60° C. to obtain 12.5 g of a productwhich was purified on a silica column using dichloroethane/ethyl acetate8/2 as eluent.

In this manner, 9.1 g of5-(2-chloro-benzyl)-2-ethyl-3-(4-hydroxybenzenesulphonyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridinewere obtained.

Yield: 45.3%

M.P.: 176° C. (hexane/isopropanol 7/3)

b)5-(2-chloro-benzyl)-2-ethyl-3-[4-{3-[N-methyl-N-(3,4-dimethoxy-β-phenethyl)amino]propyloxy}benzenesulphonyl]-4,5,6,7-tetrahydro-thieno-[3,2-c]pyridineoxalate

A mixture of 0.0031 mol of5-(2-chloro-benzyl)-2-ethyl-3-(4-hydroxybenzenesulphonyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridineand 2 g of anhydrous and crushed potassium carbonate was stirred for 0.5hour in 20 ml of N,N-dimethylformamide. After that, 0.0031 mol of1-chloro-3-[N-methyl-N-(3,4-dimethoxy-β-phenethyl)amino]propane wasadded. The medium was heated at 100° C. for 0.5 hour, cooled, pouredinto water and extracted with ethyl ether. The ethereal fraction waswashed with water, dried on anhydrous sodium sulphate and filtered. Theether was then eliminated and the oil so obtained was purified bychromatography on a silica column using ethanol as solvent to provide1.3 g of a base (61.9%). The oxalate was then formed in dry ethyletherand recrystallized from an ethyl acetate/isopropanol/diisopropyl ether.

In this manner,5-(2-chloro-benzyl)-2-ethyl-3-[4-{3-[N-methyl-N-(3,4-dimethoxy-β-phenethyl)amino]propyloxy}benzenesulphonyl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridinewas obtained.

M.P.: 110° C.

Using the same procedure as that described above5-(2-chloro-benzyl)-2-ethyl-3-{4-[3-di-n-butylamino)propyloxy]benzenesulphonyl-4,5,6,7-tetra-hydrothieno[3,2-c]pyridinedioxalate (SR 33787A) (Example 67) was obtained.

M.P.: 105° C. (isopropanol/diisopropylether).

EXAMPLE 68 Preparation of2-isopropyl-3-{4-[3-tert-butylamino)propyloxy]benzenesulphonyl}indolizinehydrochloride (SR 33712A)

This compound was obtained according to the procedure of Example 1.

Yield: 54.3%

M.P.: 198°-200° C. (ethyl acetate/methanol)

Using the same procedure,2-ethyl-3-{4-[3-di-n-butylamino)propyloxy]benzenesulphonyl}indolizineacid oxalate (SR 33711A) (Example 69) was obtained.

Yield; 75.5%

M.P.: 71-73° C. (ethyl acetate)

EXAMPLE 70 Preparation of4-{4-[3-(di-n-butylamino)propyloxy]benzenesulphonyl}-5-phenylthiazoleacid oxalate (SR 33786A)

This compound was obtained according to the procedure of Example 45.

Yield: 73%

M.P.: 110.4° C. (ethyl acetate)

EXAMPLE 71 Preparation of4-{4-[3-di-n-butylamino)propyloxy]benzenesulphonyl}-5-isopropylpyrazoleacid oxalate (SR 33789A)

This compound was obtained according to the procedure of Example 46.

M.P.: about 53° C. (methanol)

EXAMPLE 72 Preparation of4-{4-[3-(di-n-butylamino)propyloxy]benzenesulphonyl}-5-isopropyl-3-phenyl-isoxazole(SR 33758)

This compound was obtained according to the proceure of Example 48.

M.P.: 53.5° C. (toluene)

EXAMPLE 73 Preparation of2-{4-[3-(di-n-butylamino)propyloxy]benzenesulphonyl}naphthalene acidoxalate (SR 33727 A)

This compound was obtained according to the procedure of Example 49.

Yield: 75%

M.P.: 90° C. (heptane)

EXAMPLES 74 TO 78

Using the same procedure as those described above but starting from theappropriate product, the following compounds were prepared:

No 74:

2-isopropyl-3-[4-{3-[N-(3,4-dichloro-benzyl)amino]propyloxy}benzenesulphonyl]benzofuranacid oxalate.

M.P.: 198°-199° C. (methanol).

No 75:

2-isopropyl-3-[4-{3,4-dichloro-β-phenethyl)amino]propyloxy}benzenesulphonyl]benzofuranacid oxalate.

M.P.: 203°-204° C. (methanol)

No 76:

2-isopropyl-3-[4-{3-[N-[3-(1,3-benzodioxolanyl)]-β-ethyl]amino]propyloxy}benzenesulphonyl]benzeneacid oxalate.

M.P.: 164° C. (absolute ethanol).

No 77:

2-isopropyl-3-[4-{3-[N-methyl-N-(3,5-dimethoxybenzyl)amino]propyloxy}benzenesulphonyl]benzeneacid oxalate.

M.P.: 168° C. (absolute ethanol).

No 78:

2-isopropyl-3-[4-{3-[N-methyl-N-(3,4-dimethoxy-β-phenethyl)amino]propyloxy}benzenesulphonyl]-1-methyl-4,5-dihydro-pyrroleacid oxalate.

M.P.: 100°-102° C. (ethyl acetate/methanol).

EXAMPLE 79

According to known pharmaceutical techniques, a capsule containing thefollowing ingredients was prepared:

    ______________________________________                                        Ingredient           mg                                                       ______________________________________                                        Compound of the Invention                                                                          100.0                                                    Starches              99.5                                                    Colloidal silica      0.5                                                                          200.0                                                    ______________________________________                                    

We claim:
 1. An aminoalkoxyphenyl compound of formula: ##STR163## inwhich: B is selected from --S--, --SO-- and --SO₂ --,R₁ and R₂, whichare identical or different, are selected from hydrogen, methyl, ethyland halogen, A is selected from a straight- or branched-alkylene radicalhaving from 2 to 5 carbon atoms, a 2-hydroxypropylene radical, and a2-(lower alkoxy) propylene radical, R₃ is selected from C₁ -C₈ alkyl anda radical of formula:

    --Alk--Ar

in which Alk is selected from a single bond and a linear- orbranched-alkylene radical having from 1 to 5 carbon atoms; and Ar isselected from pyridyl, phenyl, 2-3-methyleneoxyphenyl,3,4-methylenedioxyphenyl and phenyl substituted with one or moresubstituents, which may be identical or different, selected from halogenatoms, C₁ -C₈ alkyl groups and C₁ -C₈ alkoxy groups, R₄ is selected fromhydrogen and C₁ -C₈ alkyl, or R₃ and R₄, when taken together, denote a1,4-tetra-methylene, 1,5-pentamethylene, 3-oxa-1,5-pentamethylene,3-aza-1,5-pentamethylene, 3-methylaza-1,5-pentamethylene,3-phenylaza-1,5-pentamethylene or --CH═CH--N═CH-- radical, R is selectedfrom hydrogen, C₁ -C₈ alkyl, C₃ -C₆, cycloalkyl, benzyl, phenyloptionally substituted with one or more substituents, which may beidentical or different, selected from halogen, C₁ -C₄ alkyl and C₁ -C₄alkoxy as well as a pharmaceutically acceptable salt thereof.
 2. Anaminoalkoxyphenyl compound of formula: ##STR164## in which: R₁ and R₂,which are identical or different, are selected from hydrogen, methyl,ethyl and halogen,A is selected from a straight- or branched-alkyleneradical having from 2 to 5 carbon atoms, a 2-hydroxypropylene radical,and a 2-(lower alkoxy)propylene radical, Alk is selected from a singlebond and a linear- or a branched-alkylene radical having from 1 to 5carbon atoms, Ar is selected from pyridyl, phenyl,2,3-methylene-dioxyphenyl, 3,4-methylenedioxyphenyl and phenylsubstituted with one or more substituents which may be identical ordifferent, selected from halogen, C₁ -C₄ alkyl and C₁ -C₄ alkoxy, R₄ isselected from hydrogen and C₁ -C₈ alkyl, R is selected from hydrogen, C₁-C₈ alkyl, C₃ -C₆ cycloalkyl, benzyl and phenyl optionally substitutedwith one or more substituents, which may be identical or different,selected from halogen, C₁ -C₄ alkyl and C₁ -C₄ alkoxy, as well as thepharmaceutically acceptable salt thereof.
 3. An aminoalkoxyphenylcompound according to claim 2 in which -Alk-Ar represents a[N-methyl-N-(3,4-dimethoxy-β-phenethyl)amino]propyloxy group.
 4. Anaminoalkoxyphenyl compound according to claim 2 in which R represents anisopropyl or cyclopropyl group.
 5. An aminoalkoxyphenyl compoundaccording to claim 1, selected from2-isopropyl-3-[4-{3-[N-methyl-N-(3,4-dimethoxy-β-phenethyl)amino]propyloxybenzenesulphonyl]indolizine and pharmaceutically acceptable salts;2-isopropyl-3-{4-[3-(tert-butylamino)propyloxy]benzenesulphonyl}indolizineand pharmaceutically acceptable salts;2-ethyl-3-{4-[3-(di-n-butylamino)propyloxy]benzenesulphony}indolizineand pharmaceutically salts.
 6. An aminoalkoxyphenyl compound accordingto claim 1 wherein the pharmaceutically acceptable salt is the oxalateor hydrochloride.
 7. An aminoalkoxyphenyl compound of formula:##STR165## in which: R₁ and R₂, which are identical or different, areselected from hydrogen, methyl, ethyl and halogen,A is selected from astraight- or branched-alkylene radical having from 2 to 5 carbon atoms,a 2-hydroxypropylene radical, and a 2-(lower alkoxy)propylene radical, Brepresents --SO₂ --, --SO-- or --S--, R₃ represents a C₁ -C₈ alkylradical, R₄ is selected from hydrogen and C₁ -C₈ alkyl or R₃ and R₄,when taken together, denote a 1,4-tetra-methylene, 1,5-pentamethylene,3-oxa-1,5-pentamethylene, 3-aza-1,5-pentamethylene,3-methylaza-1,5-pentamethylene, 3-phenylaza-1,5-pentamethylene or--CH═CH--N═CH-- radical, R is selected from hydrogen, C₁ -C₈ alkyl, C₃-C₆ cycloalkyl, benzyl, and phenyl optionally substituted with one ormore substituents, which may be identical or different, selected fromhalogen, C₁ -C₄ alkyl and C₁ -C₄ alkoxy, as well as the pharmaceuticallyacceptable salt thereof.
 8. An aminoalkoxyphenyl compound according toclaim 7, in which R represents an isopropyl or cyclopropyl group.
 9. Anaminoalkoxyphenyl compound according to claim 7, wherein thepharmaceutically acceptable salt is the oxalate or a hydrochloride. 10.A pharmaceutical or veterinary composition for use in the treatment ofangina pectoris, hypertension, arrythmia, and cerebral vascularinsufficiency, comprising an effective amount for treating anginapectoris, hypertension, arrythmia and cerebral vascular insufficiency ofat least one aminoalkoxyphenyl compound according to claim
 1. 11. Amethod of treating angina pectoris, hypertension, arrythmia and cerebralvascular insufficiency in a host in need of such treatment comprisingthe administration to this host of an effective dose of anaminoalkoxyphenyl compound according to claim
 1. 12. A compoundaccording to claim 1 whereinR is a methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, tert-butyl, 1-methylpropyl, n-pentyl, neopentyl,phenyl, monofluoro-, monochloro- or monobromophenyl, difluoro-,dichloro- or dibromophenyl, monomethyl- or dimethylphenyl, ormonomethoxy- or dimethoxyphenyl radical, a methylphenyl radicalsubstituted with a halogen atom or a cyclopropyl radical; R₃ is amethyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl,1-methylpropyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, phenyl, benzyl orphenethyl radical, a methoxyphenyl or a dimethoxyphenethyl, for example3,4-dimethoxyphenethyl radical, a dimethylphenethyl, dimethoxyphenyl,dimethoxybenzyl or pyridylethyl radical or a phenethyl radicalsubstituted in the aromatic portion, with methyl and methoxy radicals;and R₄ is a methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,tert-butyl, n-pentyl, neopentyl, n-hexyl, n-heptyl or n-octyl radical.13. A compound according to claim 2 wherein R is a methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, 1-methylpropyl,n-pentyl, neopentyl, phenyl, monofluoro-, monochloro- ormonobromophenyl, difluoro-, dichloro- or dibromophenyl, monomethyl- ordimethylphenyl, or monomethoxy- or dimethoxyphenyl radical, amethylphenyl radical substituted with a halogen atom or a cyclopropylradical;R₃ is a methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,tert-butyl, 1-methylpropyl, n-pentyl, n-hexyl, n-heptyl, n-octyl,phenyl, benzyl or phenethyl radical, a methoxyphenyl or adimethoxyphenethyl, for example 3,4-dimethoxyphenethyl radical, adimethylphenethyl, dimethoxyphenyl, dimethoxybenzyl or pyridylethylradical or a phenethyl radical substituted in the aromatic portion, withmethyl and methoxy radicals; and R₄ is a methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, neopentyl, n-hexyl,n-heptyl or n-octyl radical.
 14. A compound according to claim 7 whereinR is a methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,tert-butyl, 1-methylpropyl, n-pentyl, neopentyl, phenyl, monofluoro-,monochloro- or monobromophenyl, difluoro-, dichloro- or dibromophenyl,monomethyl- or dimethylphenyl, or monomethoxy- or dimethoxyphenylradical, a methylphenyl radical substituted with a halogen atom or acyclopropyl radical;R₃ is a methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, tert-butyl, 1-methylpropyl, n-pentyl, n-hexyl, n-heptyl,n-octyl, phenyl, benzyl or phenethyl radical, a methoxyphenyl or adimethoxyphenethyl, for example 3,4-dimethoxyphenethyl radical, adimethylphenethyl, dimethoxyphenyl, dimethoxybenzyl or pyridylethylradical or a phenethyl radical substituted in the aromatic portion, withmethyl and methoxy radicals; and R₄ is a methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, neopentyl, n-hexyl,n-heptyl or n-octyl radical.